List of phenyltropanes

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; and thusly the phenyl is attached direct to the tropane skeleton with no further spacer (therefore the name "phenyl"-tropane) that the cocaine benzoyloxy provided. The original purpose of which was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (since the methylated benzoate ester is essential to cocaine's blockage of sodium channels which cause topical anesthesia) while retaining stimulant function.^{[lower-alpha 1]} These compounds present many different avenues of research into therapeutic applications, particularly in addiction treatment. Uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's & Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.^[2]) Certain phenyltropanes can even be used as a smoking cessation aid (c.f. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers.^{[lower-alpha 2]} Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.

Troparil structure: c.f. U.S. Patent 5,496,953

2-Carboxymethyl esters (phenyl-methylecgonines)

Epibati-tropane: U.S. Patent 6,479,509 containing a nitrogen heteroatom in the benzene ring formation.

Tamagnan:^[3] displays picomolar (pM) activity for SERT

RTI-298

(4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.^[4]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.^{[lower-alpha 3]} The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.^{[lower-alpha 4]}

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (IC₅₀ values)
monohalogens (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)
Short Name i.e. Trivial IUPAC (non-systematic) Name (Singh's #)	R (para-substitution) of benzene	DA [³H]WIN 35428	5HT [³H]paroxetine	NE [³H]nisoxetine	selectivity 5-HTT/DAT	selectivity NET/DAT
cocaine (benzoyloxytropane)	H	102 ± 12 241 ± 18^ɑ	1045 ± 89 112 ± 2^b	3298 ± 293 160 ± 15^c	10.2 0.5^d	32.3 0.7^e
(para-hydrogen)phenyltropane WIN 35,065-2 (β-CPT) Troparil 11a	H	23 ± 5.0 49.8 ± 2.2^ɑ	1962 ± 61 173 ± 13^b	920 ± 73 37.2 ± 5.2^c	85.3 3.5^d	40.0 0.7^e
para-fluorophenyltropane WIN 35,428 (β-CFT) 11b	F	14 (15.7 ± 1.4) 22.9 ± 0.4^ɑ	156 (810 ± 59) 100 ± 13^b	85 (835 ± 45) 38.6 ± 9.9^c	51.6 4.4^d	53.2 1.7^e
para-nitrophenyltropane 11k	NO₂	10.1 ± 0.10	?	?	?	?
para-aminophenyltropane RTI-29^[5] 11j	NH₂	9.8 24.8 ± 1.3^g	5110	151	521.4	15.4
para-chlorophenyltropane RTI-31 11c	Cl	1.12 ± 0.06 3.68 ± 0.09^ɑ	44.5 ± 1.3 5.00 ± 0.05^b	37 ± 2.1 5.86 ± 0.67^c	39.7 1.3^d	33.0 1.7^e
para-methylphenyltropane RTI-32 Tolpane 11f	Me	1.71 ± 0.30 7.02 ± 0.30^ɑ	240 ± 27 19.38 ± 0.65^b	60 ± 0.53^e 8.42 ± 1.53^c	140 2.8^d	35.1 1.2^e
para-bromophenyltropane RTI-51 Bromopane 11d	Br	1.81 (1.69) ± 0.30	10.6 ± 0.24	37.4 ± 5.2	5.8	20.7
para-iodophenyltropane RTI-55 (β-CIT) Iometopane 11e	I	1.26 ± 0.04 1.96 ± 0.09^ɑ	4.21 ± 0.3 1.74 ± 0.23^b	36 ± 2.7 7.51 ± 0.82^c	3.3 0.9^d	28.6 3.8^e
para-hydroxyphenyltropane 11h	OH	12.1 ± 0.86	—	—	—	—
para-methoxyphenyltropane 11i	OCH₃	8.14 ± 1.3	—	—	—	—
para-azidophenyltropane 11l	N₃	2.12 ± 0.13	—	—	—	—
para-trifluoromethylphenyltropane 11m	CF₃	13.1 ± 2.2	—	—	—	—
para-acetylaminophenyltropane 11n	NHCOCH₃	64.2 ± 2.6	—	—	—	—
para-propionylaminophenyltropane 11o	NHCOC₂H₅	121 ± 2.7	—	—	—	—
para-ethoxycarbonylaminophenyltropane 11p	NHCO₂C₃H₅	316 ± 48	—	—	—	—
para-trimethylstannylphenyltropane 11q	Sn(CH₃)₃	144 ± 37	—	—	—	—
para-ethylphenyltropane RTI-83 11g	Et	55 ± 2.1	28.4 ± 3.8 (2.58 ± 3.5)	4030 (3910) ± 381 (2360 ± 230)	0.5	73.3
para-n-propylphenyltropane RTI-282ⁱ 11r	n-C₃H₇	68.5 ± 7.1	70.4 ± 4.1	3920 ± 130	1.0	57.2
para-isopropylphenyltropane 11s	CH(CH₃)₂	597 ± 52	191 ± 9.5	75000 ± 5820	0.3	126
para-vinylphenyltropane RTI-359 11t	CH-CH₂	1.24 ± 0.2	9.5 ± 0.8	78 ± 4.1	7.7	62.9
para-methylethenylphenyltropane RTI-283^j 11u	C(=CH₂)CH₃	14.4 ± 0.3	3.13 ± 0.16	1330 ± 333	0.2	92.4
para-trans-propenylphenyltropane RTI-296ⁱ 11v	trans-CH=CHCH₃	5.29 ± 0.53	11.4 ± 0.28	1590 ± 93	2.1	300
para-allylphenyltropane 11x	CH₂CH=CH₂	32.8 ± 3.1	28.4 ± 2.4	2480 ± 229	0.9	75.6
para-ethynylphenyltropane RTI-360 11y	C≡CH	1.2 ± 0.1	4.4 ± 0.4	83.2 ± 2.8	3.7	69.3
para-propynylphenyltropane RTI-281ⁱ 11z	C≡CCH₃	2.37 ± 0.2	15.7 ± 1.5	820 ± 46	6.6	346
para-cis-propenylphenyltropane RTI-304 11w	cis-CH=CHCH₃	15 ± 1.2	7.1 ± 0.71	2,800^k ± 300	0.5	186.6^k
para-(Z)-phenylethenylphenyltropane	cis-CH=CHPh	11.7 ± 1.12	—	—	—	—
para-(E)-phenylethenylphenyltropane^l RTI-436	trans–CH=CHPh	3.09 ± 0.75	335 ± 150 (30.5 ± 13.6)	1960 ± 383 (1180 ± 231)	108.4	634.3
para-phenylethynylphenyltropane^l RTI-298^[6]	–≡–Ph	3.7 ± 0.16	46.8 ± 5.8 (4.3 ± 0.53)	347 ± 25 (209 ± 15)	12.6	93.7
para-phenylpropynylphenyltropane^l^[7]	–C≡CCH₂Ph	1.82 ± 0.42	13.1 ± 1.7 (1.19 ± 0.42)	27.4 ± 2.6 (16.5 ± 1.6)	7.1	15
para-phenylbutynylphenyltropane^l RTI-430	–C≡C(CH₂)₂Ph	6.28 ± 1.25	2180 ± 345 (198 ± 31)	1470 ± 109 (885 ± 66)	347.1	234
para-(thiophen-3-yl)phenyltropane Tamagnan^[3]	p-thiophene	12	0.017	189	0.001416	15.7
para-biphenyltropane 11aa	Ph	10.3 ± 2.6^f 29.4 ± 3.8^ɑ 15.6 ± 0.6	95.8 ± 36 (8.7 ± 3.3)	1,480 ± 269 (892 ± 162)	6.1	94.8
3β-2-naphthylphenyltropane RTI-318 11bb	3β-2-naphthyl	0.51 ± 0.03 3.32 ± 0.08^f 3.53 ± 0.09^ɑ	0.80 ± 0.06	21.1 ± 1.0	1.5	41.3
para-bimethoxyphenyltropane 15	OCH₂OCH₃^h	—	—	—	—	—

^ɑ[³H]DA uptake displacement K_i value.
^b[³H]5-HT uptake displacementK_i value.
^c[³H]NE uptake displacement K_i value.

^d[³H]5-HT uptake to [³H]DA uptake ratio.
^e[³H]NE uptake to [³H]DA uptake ratio.
^fIC₅₀ for displacement of [³H]cocaine.
^gValues from alternate data-set differing from that used in rest of table.
^hOriginal source (Scheme 4, page 931, 7th of article)^[1] name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"

ⁱProtonated as the (-)—tartrate salt (isomer)
^jProtonated as the tartrate salt
^kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1^[8] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value.
^lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to an 180° extension outward from the para area of the aryl of these type of ligands.^[7]

(3′,4′-Disubstituted phenyl)-tropanes

Compound (+ S. Singh's name)	X (4′-para)	Y (3′-meta)	2 Position	config	8	DA	5-HT	NE
RTI-318 11bb	β-naphthyl		CO₂Me	β,β	NMe	0.5	0.81	20
Dichloropane (RTI-111^ɑ)^[9] 17c	Cl	Cl	CO₂Me	β,β	NMe	0.79	3.13	18.0
RTI-88 [recheck] 17e	NH₂	I	CO₂Me	β,β	NMe	1.35	1329^c	320^c
RTI-97 17d	NH₂	Br	CO₂Me	β,β	NMe	3.91	181	282
RTI-112^b 17b	Cl	Me	CO₂Me	β,β	NMe	0.82	10.5	36.2
RTI-96 17a	F	Me	CO₂Me	β,β	NMe	2.95	76	520
RTI-295	Et	I	CO₂Me	β,β	NMe	21.3	2.96	1349
RTI-353 (EINT)	Et	I	CO₂Me	β,β	NH	331	0.69	148
RTI-279	Me	I	CO₂Me	β,β	NH	5.98	1.06	74.3
RTI-280	Me	I	CO₂Me	β,β	NMe	3.12	6.81	484
Meltzer^[10]	catechol		CO₂Me	β,β	NMe	>100	?	?
Meltzer^[10]	OAc	OAc	CO₂Me	β,β	NMe	?	?	?

^ɑas ·HCl (salt)
^bas ·HCl·2 H₂O (salt)
^cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT

*Para*-*meta*-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes^[1]
Short Name (S. Singh)	Y	X	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
meta-fluorophenyltropane 16a	F	H	23 ± 7.8	-	-	-	-
meta-chlorophenyltropane 16b	Cl	H	10.6 ± 1.8	-	-	-	-
meta-bromophenyltropane 16c	Br	H	7.93 ± 0.08^ɑ	-	-	-	-
meta-iodophenyltropane 16d	I	H	26.1 ± 1.7	-	-	-	-
meta-tributylstannylphenyltropane 16e	SnBu₃	H	1100 ± 170	-	-	-	-
meta-methyl-para-fluorophenyltropane RTI-96 17a	CH₃	F	2.95 ± 0.58	-	-	-	-
meta-methyl-para-chlorophenyltropane RTI-112^c 17b	CH₃	Cl	0.81 ± 0.05	10.5 ± 0.05	36.2 ± 1.0	13.0	44.7
meta-para-dichlorophenyltropane RTI-111^b^[9] Dichloropane 17c	Cl	Cl	0.79 ± 0.08^b	3.13 ± 0.36^b	18.0 ± 0.8 17.96 ± 0.85^b^d	4.0^b	22.8^b
meta-bromo-para-aminophenyltropane RTI-97 17d	Br	NH₂	3.91 ± 0.59	181	282	46.2	72.1
meta-iodo-para-aminophenyltropane RTI-88 17e	I	NH₂	1.35 ± 0.11	120 ± 4	1329 ± 124	88.9	984
meta-iodo-para-azidophenyltropane 17f	I	N₃	4.93 ± 0.32	-	-	-	-

^ɑIC₅₀ determined in Cynomolgous monkey caudate-putamen
^bas ·HCl (salt)
^cas ·HCl·2 H₂O (salt)
^dNE_N

(2′,4′-Disubstituted phenyl)-tropanes

*Ortho*-*para*-substituted (2′,4′-disubstituted phenyltropanes)
Compound structure	Trivial IUPAC (non-systematic) Name	Y ortho	X para	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	ortho,para-dinitrophenyltropane^[11]	NO₂	NO₂	-	-	-	-	-

(3′,4′,5′-Trisubstituted para-methoxyphenyl)-tropanes

*Para*-*meta*(3′)-*meta*(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes^[12]
*Para*-methoxy/(ethoxy)-*meta*-substituted phenyltropanes
Short Name (All compounds tested as HCl salts)	X 3′-(meta)	Y 5′-(di-meta)	OR 4′-(para)	DAT IC₅₀ [³H](compound #)12	5-HTT K_i [³H]Paroxetine	NET K_i [³H]Nisoxetine	Selectivity NET/DAT Ratio K_i/IC₅₀	Selectivity NET/5-HTT Ratio K_i/K_i
Cocaine	-	-	-	89.1	95	1990	22	21
6	-	-	-	0.82 ± 0.05	0.95 ± 0.04	21.8 ± 0.6	27	23
7a 11i	H	H	CH₃	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
7b	H	H	C₂H₅	92 ± 8	1.7 ± 0.4	1690 ± 50	18	994
7c	F	H	CH₃	16 ± 1	4.8 ± 0.5	270 ± 50	17	56
7d	Br	H	CH₃	47 ± 15	3.1 ± 0.1	160 ± 20	3	52
7f	Br	Br	CH₃	92 ± 22	2.9 ± 0.1	4100 ± 400^ɑ	45	1413
7e	I	H	CH₃	170 ± 60	3.5 ± 0.4	180 ± 20	1	51
7g	I	I	CH₃	1300 ± 200	7.5 ± 0.8	180 ± 20	4	667

^ɑN=2

2-Carbmethoxy modified (replaced/substituted)

General 2-carbmethoxy modifications

2β-substitutions of p-methoxy-phenyltropanes

*Para*-OCH₃-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues^[13]
Short Name (All compounds tested as HCl salts)	CO₂R (2β-substituted) (compound 9 is 2β=R)	DAT IC₅₀ [³H](compound #)12	5-HTT K_i [³H]Paroxetine	NET K_i [³H]Nisoxetine	Selectivity NET/DAT Ratio K_i/IC₅₀	Selectivity NET/5-HTT Ratio K_i/K_i
7a 11i	CH₃	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
8a	(CH₃)₂CH	14 ± 3	135 ± 35	2010 ± 200	144	15
8b	cyclopropane	6.0 ± 2	29 ± 3	1230 ± 140	205	42
8c	cyclobutane	13 ± 3	100 ± 8	>3000	231	30
8d	O₂N…1,4-xylene…(CH₂)₂	42 ± 8	2.9 ± 0.2	330 ± 20	8	114
8e	H₂N…1,4-xylene…(CH₂)₂	7.0 ± 2	8.3 ± 0.4	2200 ± 300^ɑ	314	265
8f	CH₃CONH…1,4-xylene…(CH₂)₂	6.0 ± 1	5.5 ± 0.5	1460 ± 30	243	265
8g	H₂N…2-bromo-1,4-dimethylbenzene…(CH₂)₂	3.3 ± 1.4	4.1 ± 0.6	1850 ± 90	561	451
8h	H₂N…1,3-dibromo-2,5-dimethylbenzene…(CH₂)₂	15 ± 6	2.0 ± 0.4	2710 ± 250^ɑ	181	1360
8i	H₂N…2-iodo-1,4-dimethylbenzene…(CH₂)₂	2.5 ± 0.7	3.5 ± 1	2040 ± 300^ɑ	816	583
8j	H₂N…1,3-diiodo-2,5-dimethylbenzene…(CH₂)₂	102 ± 15	1.0 ± 0.1	2600 ± 200^ɑ	25	2600
9	3-(4-methylphenyl)-1,2-oxazole	18 ± 6	860 ± 170	>3000	167	3

^ɑN=2

2β-carboxy side-chained (p-chloro/iodo/methyl) phenyltropanes

Multi-substituted structures of 2β-ester-3β-phenyltropanes^[1]
Short Name (S. Singh)	R	X	IC₅₀ (nM) DAT [³H]WIN 35428	IC₅₀ (nM) 5-HTT [³H]paroxetine	IC₅₀ (nM) NET [³H]nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
23a	CH(CH₃)₂	H	85.1 ± 2.5	23121 ± 3976	32047 ± 1491	272	376
23b	C₆H₅	H	76.7 ± 3.6	106149 ± 7256	19262 ± 593	1384	251
24a	CH(CH₃)₂	Cl	1.4 ± 0.13 6.04 ± 0.31^ɑ	1400 ± 7 128 ± 15^b	778 ± 21 250 ± 0.9^c	1000 21.2^d	556 41.4^e
24b	cyclopropyl	Cl	0.96 ± 0.10	168 ± 1.8	235 ± 8.39	175	245
24c	C₆H₅	Cl	1.99 ± 0.05 5.25 ± 0.76^ɑ	2340 ± 27 390 ± 34^b	2960 ± 220 242 ± 30^c	1176 74.3^d	1.3 41.6^e
24d	C₆H₄-4-I	Cl	32.6 ± 3.9	1227 ± 176	967.6 ± 26.3	37.6	29.7
24e	C₆H₄-3-CH₃	Cl	9.37 ± 0.52	2153 ± 143	2744 ± 140	230	293
24f	C₆H₄-4-CH₃	Cl	27.4 ± 1.5	1203 ± 42	1277 ± 118	43.9	46.6
24g	C₆H₄-2-CH₃	Cl	3.91 ± 0.23	3772 ± 384	4783 ± 387	965	1223
24h	C₆H₄-4-Cl	Cl	55 ± 2.3	16914 ± 1056	4883 ± 288	307	88.8
24i	C₆H₄-4-OCH₃	Cl	71 ± 5.6	19689 ± 1843	1522 ± 94	277	21.4
24j	(CH₂)₂C₆H₄-4-NO₂	Cl	2.71 ± 0.13	-	-	-	-
24k	(CH)₂C₆H₄-4-NH₂	Cl	2.16 ± 0.25	-	-	-	-
24l	(CH₂)₂C₆H₃-3-I-4-NH₂	Cl	2.51 ± 0.25	-	-	-	-
24m	(CH₂)₂C₆H₃-3-I-4-N₃	Cl	14.5 ± 0.94	-	-	-	-
24n	(CH₂)₂C₆H₄-4-N₃	Cl	6.17 ± 0.57	-	-	-	-
24o	(CH₂)₂C₆H₄-4-NCS	Cl	5.3 ± 0.6	-	-	-	-
24p	(CH₂)₂C₆H₄-4-NHCOCH₂Br	Cl	1.73 ± 0.06	-	-	-	-
25a	CH(CH₃)₂	I	0.43 ± 0.05 2.79 ± 0.13^ɑ	66.8 ± 6.53 12.5 ± 1.0^b	285 ± 7.6 41.2 ± 3.0^c	155 4.5^d	663 14.8^e
25b	cyclopropyl	I	0.61 ± 0.08	15.5 ± 0.72	102 ± 11	25.4	167
25c	C₆H₅	I	1.51 ± 0.34 6.85 ± 0.93^ɑ	184 ± 22 51.6 ± 6.2^b	3791 ± 149 32.7 ± 4.4^c	122 7.5^d	2510 4.8^e
26a	CH(CH₃)₂	CH₃	6.45 ± 0.85 15.3 ± 2.08^ɑ	6090 ± 488 917 ± 54^b	1926 ± 38 73.4 ± 11.6^c	944 59.9^d	299 4.8^e
26b	CH(C₂H₅)₂	CH₃	19.1 ± 1	4499 ± 557	3444 ± 44	235	180
26c	cyclopropyl	CH₃	17.8 ± 0.76	485 ± 21	2628 ± 252	27.2	148
26d	cyclobutyl	CH₃	3.74 ± 0.52	2019 ± 133	4738 ± 322	540	1267
26e	cyclopentyl	CH₃	1.68 ± 0.14	1066 ± 109	644 ± 28	634	383
26f	C₆H₅	CH₃	3.27 ± 0.06 9.13 ± 0.79^ɑ	24500 ± 1526 1537 ± 101^b	5830 ± 370 277 ± 23^c	7492 168^d	1783 30.3^e
26g	C₆H₄-3-CH₃	CH₃	8.19 ± 0.90	5237 ± 453	2136 ± 208	639	261
26h	C₆H₄-4-CH₃	CH₃	81.2 ± 16	15954 ± 614	4096 ± 121	196	50.4
26i	C₆H₄-2-CH₃	CH₃	23.2 ± 0.97	11040 ± 504	25695 ± 1394	476	1107
26j	C₆H₄-4-Cl	CH₃	117 ± 7.9	42761 ± 2399	9519 ± 864	365	81.3
26k	C₆H₄-4-OCH₃	CH₃	95.6 ± 8.8	82316 ± 7852	3151 ± 282	861	33.0

^ɑKi value for displacement of [³H]DA uptake.
^bKi value for displacement of [³H]5-HT uptake.
^cKi value for displacement of [³H]NE uptake.
^d[³H]5-HT uptake to [³H]DA uptake ratio.
^e[³H]NE uptake to [³H]DA uptake ratio.

Carboxyaryl

Compound	X	2 Position	config	8	DA	5-HT	NE
RTI-122	I	-CO₂Ph	β,β	NMe	1.50	184	3,791
RTI-113	Cl	-CO₂Ph	β,β	NMe	1.98	2,336	2,955
RTI-277	NO₂	-CO₂Ph	β,β	NMe	5.94	2,910	5,695
RTI-120 [recheck]	Me	-CO₂Ph	β,β	NMe	3.26	24,471	5,833
RTI-116	Cl	-CO₂(p-C₆H₄I)	β,β	NMe	33	1,227	968
RTI-203	Cl	CO₂(m-C₆H₄Me)	β,β	NMe	9.37	2153	2744
RTI-204	Cl	-CO₂(o-C₆H₄Me)	β,β	NMe	3.91	3,772	4,783
RTI-205	Me	-CO₂(m-C₆H₄Me)	β,β	NMe	8.19	5,237	2,137
RTI-206	Cl	-CO₂(p-C₆H₄Me)	β,β	NMe	27.4	1,203	1,278

2-Phenyl-3-Phenyltropanes

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake^[1]
Short Name (S. Singh)	Stereochemistry	X (para)	DAT [³H]WIN 35428 IC₅₀ (nM)	DAT [³H]Mazindol K_i (nM)	5-HTT [³H]Paroxetine IC₅₀ (nM)	[³H]DA uptake K_i (nM)	[³H]5-HT uptake K_i (nM)	Selectivity [³H]5-HT/[³H]DA
Cocaine	(2β,3β)	(H)	89 ± 4.8	281	1050 ± 89	423	155	0.4
67a	2β,3β	H	12.6 ± 1.8	14.9	21000 ± 3320	28.9	1100	38.1
67b	2β,3α	H	-	13.8	-	11.7	753	64.3
67c	2α,3α	H	690 ± 37	-	41300 ± 5300	-	-	-
68	2β,3α	F	-	6.00	-	4.58	122	26.6
69a	2β,3β	CH₃	1.96 ± 0.08	2.58	11000 ± 83	2.87	73.8	25.7
69b	2β,3α	CH₃	-	2.87	-	4.16	287	69.0
69c	2α,3α	CH₃	429 ± 59	-	15800 ± 3740	-	-	-

Carboxyalkyl

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-77	Cl	CH₂C₂(3-iodo-p-anilino)	β,β	NMe	2.51	—	2247
RTI-121 IPCIT	I	-CO₂Prⁱ	β,β	NMe	0.43	66.8	285
RTI-153	I	-CO₂Prⁱ	β,β	NH	1.06	3.59	132
RTI-191	I	-CO₂Pr^cyc	β,β	NMe	0.61	15.5	102
RTI-114	Cl	-CO₂Prⁱ	β,β	NMe	1.40	1,404	778
RTI-278	NO₂	-CO₂Prⁱ	β,β	NMe	8.14	2,147	4,095
RTI-190	Cl	-CO₂Pr^cyc	β,β	NMe	0.96	168	235
RTI-193	Me	-CO₂Pr^cyc	β,β	NMe	1.68	1,066	644
RTI-117	Me	-CO₂Prⁱ	β,β	NMe	6.45	6,090	1,926
RTI-150	Me	-CO₂Bu^cyc	β,β	NMe	3.74	2,020	4,738
RTI-127	Me	-CO₂C(H)Et₂	β,β	NMe	19	4500	3444
RTI-338	ethyl	-CO₂C₂Ph	β,β	NMe	1104	7.41	3366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a ^cycBu resulted in greater DAT selectivity than did the ^cycPr homologue.

2-Alkyl Esters & Ethers

Esters (2-Alkyl)

2β-Alkyl Ester Phenyltropanes^[1]
Short Name (S. Singh)	2β=R	K_i (nM) DAT [³H]WIN 35428	IC₅₀ (nM) [³H]DA uptake	Selectivity uptake/binding
59a	CH=CHCO₂CH₃	22 ± 2	123 ± 65	5.6
59b	CH₂CH₂CO₂CH₃	23 ± 2	166 ± 68	7.2
59c	(CH₂)₂CH=CHCO₂CH₃	20 ± 2	203 ± 77	10.1
59d	(CH₂₂)₄CO₂CH₃	30 ± 2	130 ± 7	4.3
59e	CH=CHCH₂OH	26 ± 3	159 ± 43	6.1
59f	CH₂CH₂CH₂OH	11 ± 1	64 ± 32	5.8
59g	CH₂CH₂COC₆H₅	28 ± 2	47 ± 15	1.7

Ethers (2-Alkyl)

2-Alkyl Ether Phenyltropanes^[1]
Short Name (S. Singh)	Stereochemistry	DAT [³H]WIN 35428 IC₅₀ (nM)	5-HTT [³H]Paroxetine IC₅₀ (nM)	NET [³H]Nisoxetine IC₅₀ (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
Paroxetine		623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
R-60a	2β,3β	308 ± 20	294 ± 18	5300 ± 450	0.9	17.2
R-60b	2α,3β	172 ± 8.8	52.9 ± 3.6	26600 ± 1200	0.3	155
R-60c	2β,3α	3.01 ± 0.2	42.2 ± 16	123 ± 9.5	14.1	40.9
S-60d	2β,3β	1050 ± 45	88.1 ± 2.8	27600 ± 1100	0.08	26.3
S-60e	2α,3β	1500 ± 74	447 ± 47	2916 ± 1950	0.3	1.9
S-60f	2β,3α	298 ± 17	178 ± 13	12400 ± 720	0.6	41.6

Carboxamides

U.S. Patent 5,736,123

Structure	Code (S. Singh #)	X	2 Position	config	8	DA [³H]WIN 35428 (IC₅₀ nM)	NE [³H]nisoxetine	5-HT [³H]paroxetine (IC₅₀ nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	RTI-106 27b	Cl	CON(H)Me	β,β	NMe	12.4 ± 1.17	1584 ± 62	1313 ± 46	106	128
	RTI-118 27a	Cl	CONH₂	β,β	NMe	11.5 ± 1.6	4270 ± 359	1621 ± 110	141	371
	RTI-222 29d	Me	morpholinyl	β,β	NMe	11.7 ± 0.87	23601 ± 1156	>100K	>8547	2017
	RTI-129 27e	Cl	CONMe₂	β,β	NMe	1.38 ± 0.1	942 ± 48	1079 ± 102	792	683
	RTI-146 27d	Cl	CONHCH₂OH	β,β	NMe	2.05 ± 0.23	144 ± 3	97.8 ± 10	47.7	70.2
	RTI-147 27i	Cl	CON(CH₂)₄	β,β	NMe	1.38 ± 0.03	3,950 ± 72	12400 ± 1207	8985	2862
	RTI-156	Cl	CON(CH₂)₅	β,β	NMe	6.61	5832	3468
	RTI-170	Cl	CON(H)CH₂C≡CH	β,β	NMe	16.5	1839	4827
	RTI-172	Cl	CON(H)NH₂	β,β	NMe	44.1	3914	3815
	RTI-174	Cl	CONHCOMe	β,β	NMe	158	>43K	>125K
	RTI-182	Cl	CONHCH₂COPh	β,β	NMe	7.79	1722	827
	RTI-183✲ 27g	Cl	CON(OMe)Me	β,β	NMe	0.85 ± 0.06	549 ± 18.5	724 ± 94	852	646
	RTI-186 29c	Me	CON(OMe)Me	β,β	NMe	2.55 ± 0.43	422 ± 26	3402 ± 353	1334	165
	RTI-198 27h	Cl	CON(CH₂)₃	β,β	NMe	6.57 ± 0.67	990 ± 4.8	814 ± 57	124	151
	RTI-196 27c	Cl	CONHOMe	β,β	NMe	10.7 ± 1.25	9907 ± 632	43700 ± 1960	4084	926
	RTI-201	Cl	CONHNHCOPh	β,β	NMe	91.8	>20K	>48K
	RTI-208 27j	Cl	CONO(CH₂)₃	β,β	NMe	1.47 ± 0.13	1083 ± 76	2470 ± 56	1680	737
	RTI-214 27l	Cl	CON(-CH₂CH₂-)₂O	β,β	NMe	2.90 ± 0.3	8545 ± 206	88769 ± 1855	30610	2946
	RTI-215 27f	Cl	CONEt₂	β,β	NMe	5.48 ± 0.19	5532 ± 299	9433 ± 770	1721	1009
	RTI-217	Cl	CONH(m-C₆H₄OH)	β,β	NMe	4.78	>30K	>16K
	RTI-218✲	Cl	CON(Me)OMe	β,β	NMe	1.19	520	1911
	RTI-226 27m	Cl	CONMePh	β,β	NMe	45.5 ± 3	2202 ± 495	23610 ± 2128	519	48.4
	RTI-227	I	CONO(CH₂)₃	β,β	NMe	0.75	446	230
	RTI-229^[14] 28a	I	CON(CH₂)₄	β,β	NMe	0.37 ± 0.04	991 ± 21	1728 ± 39	4670	2678
	27k					6.95 ± 1.21	1752 ± 202	3470 ± 226	499	252
	28b					1.08 ± 0.15	103 ± 6.2	73.9 ± 8.1	68.4	95.4
	28c					0.75 ± 0.02	357 ± 42	130 ± 15.8	173	476
	29a					41.8 ± 2.45	4398 ± 271	6371 ± 374	152	105
	29b					24.7 ± 1.93	6222 ± 729	33928 ± 2192	1374	252

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

2β-Carboxamide-3β-Phenyltropanes^[1]
Short Name (S. Singh)	R	X	IC₅₀ (nM) DAT [³H]WIN 35428	IC₅₀ (nM) 5-HTT [³H]Paroxetine	IC₅₀ (nM) NET [³H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT

29a	NH₂	CH₃	41.8 ± 2.45	6371 ± 374	4398 ± 271	152	105
29b	N(CH₂CH₃)₂	CH₃	24.7 ± 1.93	33928 ± 2192	6222 ± 729	1374	252
29c	N(OCH₃)CH₃	CH₃	2.55 ± 0.43	3402 ± 353	422 ± 26	1334	165
29d	4-morpholine	CH₃	11.7 ± 0.87	>100000	23601 ± 1156	>8547	2017

Heterocycles

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize^[15] to the energetically more favorable trans configuration. This can happen to cocaine also.

Atomic positions A—C
(compound model 34)

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔV_min(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔV_min(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔV_min is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.^{[lower-alpha 5]}

3-Substituted-isoxazol-5-yl

N-methylphenyltropanes with 1R β,β stereochemistry.
Code (S.S. #)	X	R	DA	NE	5HT
RTI-165	Cl	3-methylisoxazol-5-yl	0.59	181	572
RTI-171	Me	3-methylisoxazol-5-yl	0.93	254	3818
RTI-180	I	3-methylisoxazol-5-yl	0.73	67.9	36.4
RTI-177 β-CPPIT 32g	Cl	3-phenylisoxazol-5-yl	1.28 ± 0.18	504 ± 29	2420 ± 136
RTI-176	Me	3-phenylisoxazol-5-yl	1.58	398	5110
RTI-181	I	3-phenylisoxazol-5-yl	2.57	868	100
RTI-184	H	methyl	43.3	—	6208
RTI-185	H	Ph	285	—	>12K
RTI-334	Cl	3-ethylisoxazol-5-yl	0.50	120	3086
RTI-335	Cl	isopropyl	1.19	954	2318
RTI-336	Cl	3-(4-methylphenyl)isoxazol-5-yl	4.09	1714	5741
RTI-337	Cl	3-t-butyl-isoxazol-5-yl	7.31	6321	37K
RTI-345	Cl	p-chlorophenyl	6.42	5290	>76K
RTI-346	Cl	p-anisyl	1.57	762	5880
RTI-347	Cl	p-fluorophenyl	1.86	918	7257
RTI-354	Me	3-ethylisoxazol-5-yl	1.62	299	6400
RTI-366	Me	R = isopropyl	4.5	2523 (1550)	42,900 (3900)
RTI-371	Me	p-chlorophenyl	8.74	>100K (60,200)	>100K (9090)
RTI-386	Me	p-anisyl	3.93	756 (450)	4027 (380)
RTI-387	Me	p-fluorophenyl	6.45	917 (546)	>100K (9400)

3-Substituted-1,2,4-oxadiazole

RTI-155

Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.
Code (Singh's #)	X	R	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	NET (IC₅₀ nM) [H³]nisoxetine	5-HTT (IC₅₀ nM) [H³]paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
ααRTI-87	H	3-methyl-1,2,4-oxadiazole	204	36K	30K
βαRTI-119	H	3-methyl-1,2,4-oxadiazole	167	7K	41K
αβRTI-124	H	3-methyl-1,2,4-oxadiazole	1028	71K	33K
RTI-125 (32a)	Cl	3-methyl-1,2,4-oxadiazole	4.05 ± 0.57	363 ± 36	2584 ± 800	637	89.6
ββRTI-126^[16] (31)	H	3-methyl-1,2,4-oxadiazole	100 ± 6	7876 ± 551	3824 ± 420	38.3	788
RTI-130 (32c)	Cl	3-phenyl-1,2,4-oxadiazole	1.62 ± 0.02	245 ± 13	195 ± 5	120	151
RTI-141 (32d)	Cl	3-(p-anisyl)-1,2,4-oxadiazole	1.81 ± 0.19	835 ± 8	337 ± 40	186	461
RTI-143 (32e)	Cl	3-(p-chlorophenyl)-1,2,4-oxadiazole	4.06 ± 0.22	40270 ± 180 (4069)	404 ± 56	99.5	9919
RTI-144 (32f)	Cl	3-(p-bromophenyl)-1,2,4-oxadiazole	3.44 ± 0.36	1825 ± 170	106 ± 10	30.8	532
βRTI-151 (33)	Me	3-phenyl-1,2,4-oxadiazole	2.33 ± 0.26	60 ± 2	1074 ± 130	459	25.7
αRTI-152	Me	3-phenyl-1,2,4-oxadiazole	494	—	1995
RTI-154 (32b)	Cl	3-isopropyl-1,2,4-oxadiazole	6.00 ± 0.55	135 ± 13	3460 ± 250	577	22.5
RTI-155	Cl	3-cyclopropyl-1,2,4-oxadiazole	3.41	177	4362

RTI-4229-470 structure.^[17]

↑ above: 2D skeletal depiction.

↓ below: 3D tube model.

N-methylphenyltropanes with 1R β,β stereochemistry.
Code	X	2 Group	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	NET (IC₅₀ nM) displacement of [H³]nisoxetine	5-HTT (IC₅₀ nM) displacement of [H³]paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
RTI-157	Me	tetrazole	1557	>37K	>43K
RTI-163	Cl	tetrazole	911	—	5456
RTI-178	Me	5-phenyl-oxazol-2-yl	35.4	677	1699
RTI-188	Cl	5-phenyl-1,3,4-oxadiazol-2-yl	12.6	930	3304
RTI-189 (32i)	Cl	5-phenyl-oxazol-2-yl	19.7 ± 1.98	496 ± 42	1120 ± 107	56.8	25.5
RTI-194	Me	5-methyl-1,3,4-oxadiazol-2-yl	4.45	253	4885
RTI-195	Me	5-phenyl-1,3,4-oxadiazol-2-yl	47.5	1310	>22,000
RTI-199	Me	5-phenyl-1,3,4-thiadiazol-2-yl	35.9	>24,000	>51,000
RTI-200	Cl	5-phenyl-1,3,4-thiadiazol-2-yl	15.3	4142	>18,000
RTI-202	Cl	benzothiazol-2-yl	1.37	403	1119
RTI-219	Cl	5-phenylthiazol-2-yl	5.71	8516	10,342
RTI-262	Cl
RTI-370	Me	3-(p-cresyl)isoxazol-5-yl	8.74	6980	>100K
RTI-371	Cl	3-(p-chlorophenyl)isoxazol-5-yl	13	>100K	>100K
RTI-436	Me	-CH=CHPh^[18]	3.09	1960 (1181)	335 (31)
RTI-470	Cl	o-Cl-benzothiazol-2-yl	0.094	1590 (994)	1080 (98)
RTI-451	Me	benzothiazol-2-yl	1.53	476 (287)	7120 (647)
32g			1.28 ± 0.18	504 ± 29	2420 ± 136	1891	394
32h			12.6 ± 10.3	929 ± 88	330 ± 196	262	73.7

Above is taken from: RTI, Kuhar, et al. U.S. Patent 5,935,953 (1999).

N.B There are some alternative ways of making the tetrazole ring however; C.f. the sartan drugs synthesis schemes. Bu₃SnN₃ is a milder choice of reagent than hydrogen azide (c.f. Irbesartan).

Acyl (C2-propanoyl)

# (#)	X	Y	2 Position	config	8	DA	5-HT	NE
WF-23 (39n)	β-naphthyl		C(O)Et	β,β	NMe	0.115	0.394	No data
WF-31 PIT	-Prⁱ	H	C.O.Et	β,β	NMe	615	54.5	No data
WF-11^✲ PTT (39e)	Me	H	-C.O.Et	β,β	NMe	8.2	131	No data
WF-25 (39a)	H	H	-C.O.Et	β,β	NMe	48.3	1005	No data
WF-33	6-MeoBN		C(O)Et	α,β	NMe	0.13	2.24	No data
^✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)

2β-acyl-3β-phenyltropane structures^{[lower-alpha 6]}
S. Singh's alphanumeric assignation (name)	R₁	R₂	DAT [¹²⁵I]RTI-55 IC₅₀ (nM)	5-HTT [³H]Paroxetine K_i (nM)	Selectivity 5-HTT/DAT
cocaine			173 ± 19	—	—
Troparil 11a (WIN 35065-2)			98.8 ± 12.2	—	—
WF-25 39a	C₂H₅	C₆H₅	48.3 ± 2.8	1005 ± 112	20.8
39b	CH₃	C₆H₅	114 ± 22	1364 ± 616	12.0
39c	C₂H₅	C₆H₄-4-F	15.3 ± 2.8	630 ± 67	41.2
39d	CH₃	C₆H₄-4-F	70.8 ± 13	857 ± 187	12.1
WF-11 39e	C₂H₅	C₆H₄-4-CH₃	8.2 ± 1.6	131 ± 1	16.0
(+)-39e	C₂H₅	C₆H₄-4-CH₃	4.21 ± 0.05	74 ± 12	17.6
(-)-39e	C₂H₅	C₆H₄-4-CH₃	1337 ± 122	>10000	—
39f	CH₃	C₆H₄-4-CH₃	9.8 ± 0.5	122 ± 22	12.4
39g	CH₃	C₆H₄-4-C₂H₅	152 ± 24	78.2 ± 22	0.5
39h	C₂H₅	C₆H₄-4-CH(CH₃)₂	436 ± 41	35.8 ± 4.4	0.08
39i	C₂H₅	C₆H₄-4-C(CH₃)₃	2120 ± 630	1771 ± 474	0.8
39j	C₂H₅	C₆H₄-4-C₆H₅	2.29 ± 1.08	4.31 ± 0.01	1.9
39k	C₂H₅	C₆H₄-2-CH₃	1287 ± 322	710000	>7.8
39l	C₂H₅	1-naphthyl	5.43 ± 1.27	20.9 ± 2.9	3.8
39m	CH₃	1-naphthyl	10.1 ± 2.2	25.6 ± 5.1	2.5
WF-23 39n	C₂H₅	2-naphthyl	0.115 ± 0.021	0.394 ± 0.074	3.5
39o	CH₃	2-naphthyl	0.28 ± 0.11	1.06 ± 0.36	3.8
39p	C₂H₅	C₆H₄-4-CH(C₂H₅)₂	270 ± 38	540 ± 51	2.0
39q	C₂H₅	C₆H₄-4-C₆H₁₁	320 ± 55	97 ± 12	0.30
39r	C₂H₅	C₆H₄-4-CH=CH₂	0.90 ± 0.34	3.2 ± 1.3	3.5
39s	C₂H₅	C₆H₄-4-C(=CH₂)CH₃	7.2 ± 2.1	0.82 ± 0.38	0.1

Ester reduction

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-100	F	-CH₂OH	β,β	NMe	47	4741	no data
RTI-101	I	-CH₂OH	β,β	NMe	2.2	26	no data
RTI-99	Br	-CH₂OH	β,β	NMe	1.49	51	no data
RTI-93	Cl	-CH₂OH	β,β	NMe	1.53	204	43.8
RTI-105	Cl	-CH₂OAc	β,β	NMe	1.60	143	127
RTI-123	Cl	-CH₂OBz	β,β	NMe	1.78	3.53	393
RTI-145	Cl	-CH₂OCO₂Me	β,β	NMe	9.60	2.93	1.48

2-Alkane/Alkene

2-Alkane/Alkene-3-Phenyltropanes
Singh's #	R	X	DAT mazindol displacement	DA uptake	5-HT Uptake	Selectivity DA uptake/DAT binding
11a WIN 35062-2			89.4	53.7	186	0.6
11c			0.83 ± 00.7	28.5 ± 0.9	—	34.3
11f			5.76	6.92	23.2	1.2
41a	(CH₂)₂CH₃	H	12.2	6.89	86.8	0.6
41b	(CH₂)₃C₆H₅	H	16 ± 2^a	43 ± 13^b	—	2.7
42	(CH₂)₂CH₃	F	5.28	1.99	21.7	0.4
43a	CH=CH₂	Cl	0.59 ± 0.15	2.47 ± 0.5	—	4.2
43b	E-CH=CHCl	Cl	0.42 ± 0.04	1.13 ± 0.27	—	2.7
43c	Z-CH=CHCl	Cl	0.22 ± 0.02	0.88 ± 0.05	—	4.0
43d	E-CH=CHC₆H₅	Cl	0.31 ± 0.04	0.66 ± 0.01	—	2.1
43e	Z-CH=CHC₆H₅	Cl	0.14 ± 0.07	0.31 ± 0.09	—	2.2
43f	CH₂CH₃	Cl	2.17 ± 0.20	2.35 ± 0.52	—	1.1
43g	(CH₂)₂CH₃	Cl	0.94 ± 0.08	1.08 ± 0.05	—	1.1
43h	(CH₂)₃CH₃	Cl	1.21 ± 0.18	0.84 ± 0.05	—	0.7
43i	(CH₂)₅CH₃	Cl	156 ± 15	271 ± 3	—	1.7
43j	(CH₂)₂C₆H₅	Cl	1.43 ± 0.03	1.54 ± 0.08	—	1.0
44a	(CH₂)₂CH₃	CH₃	1.57	1.10	10.3	0.7
44b	(CH₂)₃CH₃	CH₃	1.82	1.31	15.1	0.7
45	(CH₂)₂CH₃	H	74.9	30.2	389	0.4
46	(CH₂)₂CH₃	F	21.1	12.1	99.6	0.6
47a	(CH₂)₂CH₃	CH₃	8.91	11.8	50.1	1.3
47b	(CH₂)₃CH₃	CH₃	11.4	10.1	51.0	0.9

^aK_i value for displacement of WIN 35428.
^bIC₅₀ value.

Irreversible covalent (cf. ionic) C2 ligands

Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. )^[19] RTI-76:^[20] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

Note the contrast to the phenylisothiocyanate covalent binding site location as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

Benztropine based (C2-position hetero-substituted) phenyltropanes

Benztropine phenyltropane:^[21]

F&B series (Biotin side-chains etc.)

One patent claims a series of compounds with biotin-related sidechains are pesticides.^[16]

Code	para-X	C2-Tropane Position	config	DA	NE	5-HT
RTI-224	Me	F1^c	β,β	4.49	—	155.6
RTI-233	Me	F2	β,β	4.38	516	73.6
RTI-235	Me	F3 d	β,β	1.75	402	72.4
RTI-236	Me	B1 d	β,β	1.63	86.8	138
RTI-237	Me	B2 d	β,β	7.27	258	363
RTI-244	Me	B3 d	β,β	15.6	1809	33.7
RTI-245	Cl	F4 c	β,β	77.3	—	—
RTI-246	Me	F4 c	β,β	50.3	3000	—
RTI-248	Cl	F6 c	β,β	9.73	4674	6.96
RTI-249	Cl	F1 c	β,β	8.32	5023	81.6
RTI-266	Me	F2	β,β	4.80	836	842
RTI-267	Me	F7 wrong	β,β	2.52	324	455
RTI-268	Me	F7 right	β,β	3.89	1014	382
RTI-269	Me	F8	β,β	5.55	788	986

Miscellany (i.e. Misc./Miscellaneous) C2-substituents

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-102	I	CO₂H	β,β	NMe	474	1928	43,400
RTI-103	Br	CO₂H	β,β	NMe	278	3070	17,400
RTI-104	F	CO₂H	β,β	NMe	2744	>100K	>100K
RTI-108	Cl	-CH₂Cl	β,β	NMe	2.64	98	129.8
RTI-241	Me	-CH₂CO₂Me	β,β	NMe	1.02	619	124
RTI-139	Cl	-CH₃	β,β	NMe	1.67	85	57
RTI-161	Cl	-C≡N	β,β	NMe	13.1	1887	2516
RTI-230	Cl	H₃C–C=CH₂	β,β	NMe	1.28	57	141
RTI-240	Cl	-CHMe₂	β,β	NMe	1.38	38.4	84.5
RTI-145	Cl	-CH₂OCO₂Me	β,β	NMe	9.60	2,932	1,478
RTI-158	Me	-C≡N	β,β	NMe	57	5095	1624
RTI-131	Me	-CH₂NH₂	β,β	NMe	10.5	855	120
RTI-164	Me	-CH₂NHMe	β,β	NMe	13.6	2246	280
RTI-132	Me	-CH₂NMe₂	β,β	NMe	3.48	206	137
RTI-239	Me	-CHMe₂	β,β	NMe	0.61	114	35.6
RTI-338	Et	-CO₂CH₂Ph	β,β	NMe	1104	7.41	3366
RTI-348	H	-Ph	β,β	NMe	28.2	>34,000	2670

C2-truncated/descarboxyl (non-ecgonine w/o 2-position-replacement tropanes)

Aryl-Tropenes

WO2004113297

Test compound	DA-uptake IC₅₀(μM)	NA-uptake IC₅₀(μM)	5-HT-uptake IC₅₀(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene	0.26	0.028	0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene	0.058	0.013	0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene	0.034	0.018	0.00023

WO 9713770

8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES
Test Compound	DA uptake IC₅₀(μM)	NE uptake IC₅₀(μM)	5-HT uptake IC₅₀(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	0.079	0.026	0.0047

U.S. Patent 2,001,047,028

Test Compound	DA uptake IC₅₀(μM)	NE uptake IC₅₀(μM)	5-HT uptake IC₅₀(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	18	4.9	0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	1.5	0.5	0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	22.00	8.00	0.0036

3-Aryl bicyclo[3.2.1]octanes^[1]
Compound # (S. Singh)	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram	Selectivity 5-HTT/DAT
R/S-98a	7.1 ± 1.7	5160 ± 580	726
R/S-98b	9.6 ± 1.8	33.4 ± 0.6	3.5
R/S-98c	14.3 ± 1.1	180 ± 65	12.6

Pseudotropinearylethers

U.S. Patent 4,861,889

Enantioselective nonstandard configurations (non-2β-,3β-)

β,α Stereochemistry

Structure	Compound (RTI #) (S. Singh's #)	X	2 Group	config	8	DAT IC₅₀ (nM) [³H]WIN 35428	5-HTT IC₅₀ (nM) [³H]paroxetine	NET IC₅₀ (nM) [³H]nisoxetine	selectivity 5-HTT/DAT	selectivity NET/DAT
	RTI-140 20a	H	CO₂Me	β,α	NMe	101 ± 16	5,701 ± 721	2,076 ± 285	56.4	20.6
	RTI-352^ɑ 20d	I	CO₂Me	β,α	NMe	2.86 ± 0.16	64.9 ± 1.97	52.4 ± 4.9	22.8	18.4
	RTI-549	Br	CO₂Me	β,α	NMe	—	—	—	—	—
	RTI-319^b	BN	CO₂Me	β,α	NMe	1.1	11.4	70.2	—	—
	RTI-286^c 20b	F	CO₂Me	β,α	NMe	21 ± 0.57	5062 ± 485	1231 ± 91	241	58.6
	RTI-274^d	F	CH₂O(3′,4′-MD-phenyl)	β,α	NH	3.96	5.62	14.4	—	—
	RTI-287	Et	CO₂Me	β,α	NMe	327	1687	17,819	—	—
	20c	Cl	CO₂Me	β,α	NMe	2.4 ± 0.2	998 ± 120	60.1 ± 2.4	416	25.0
	20e	Me	CO₂Me	β,α	NMe	10.2 ± 0.08	4250 ± 422	275 ± 24	417	27.0
	RTI-319	3α-2-naphthyl	CO₂Me	β,α	NMe	1.1 ± 0.09	11.4 ± 1.3	70.2 ± 6.28	—	—

^ɑU.S. Patent 6,358,492^bU.S. Patent 7,011,813^cU.S. Patent 7,011,813^dU.S. Patent 7,291,737

α,β Stereochemistry

CA 2112084

Compound	DA (μM)	M.E.D. (mg/kg)	Dose (mg/kg)	Activity	Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane	0.39	<1	50	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane	0.1	1	25	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane	0.016	0.25	50	+	+++

di-chloro; para- & meta- in tandem (α,β configured phenyltropanes)

U.S. Patent 2,001,047,028

Compound	X	2 Group	config	8	DA	5-HT	NE
Brasofensine	Cl₂	methyl aldoxime	α,β	NMe	—	—	—
Tesofensine	Cl₂	ethoxymethyl	α,β	NMe	65	11	1.7
NS-2359 (GSK-372,475)	Cl₂	Methoxymethyl	α,β	NH	—	—	—

fumaric acid salts (of α,β configured phenyltropanes)

A1 WO 2004072075 A1

Test Compound	DA uptake IC₅₀(μM)	NE uptake IC₅₀(μM)	5-HT uptake IC₅₀(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.035	0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.15	0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.10	0.048	0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.088	0.051	0.013

Arene equivalent alterations

η⁶-3β-(transition metal complexed phenyl)tropanes

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η⁶-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.^[1] (cf. the Dewar–Chatt–Duncanson model)

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity K_i values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.^[1]

Displacement of Receptor-Bound [³H]WIN 35428 and Inhibition of [³H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes^[1]
Compound # (S. Singh) Systematic name	K_i (nM)^ɑ	IC₅₀ (nM)	selectivity binding/uptake
Cocaine	32 ± 5 388 ±221	405	12.6
11a	33 ± 17 314 ± 222	373	11.3
21a^c	17 ± 15^b 224 ± 83	418	24.6
21b^d	2280 ± 183	3890	1.7

^ɑThe binding data fit a two-site model better than a one-site model
^bThe K_i value for the one-site model was 124 ± 10 nM
^cIUPAC: [η⁶-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
^dIUPAC: [η⁵-(pentamethylcyclopentadienyl)]-[η⁶-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

3-(2-thiophene) and 3-(2-furan)

U.S. Patent 7,247,643

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt	0.30	0.0019	0.00052
2	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.36	0.0036	0.00042
3	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.31	0.00090	0.00036
4	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.92	0.0030	0.00053
5	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.074	0.0018	0.00074
6	(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.19	0.0016	0.00054

Thiophenyltropanes

Diaryl

Hanna et al. (2007)^[22]	ZIENT:^[23]

6/7-tropane position substituted

2β-carbmethoxy 6/7 substituted

6/7-Substituted 2-carbomethoxy-phenyltropanes^[1]
Compound # (S. Singh)	Substitution	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram	Selectivity 5-HTT/DAT
Cocaine	H	65 ± 12	-	-
103a	3β,2β, 7-OMe 3′,4′-Cl₂	86 ± 4.7	884 ± 100	10.3
103b	3β,2β, 7-OH 3′,4′-Cl₂	1.42 ± 0.03	28.6 ± 7.8	20.1
103c	3α,2β, 7-OH 3′,4′-Cl₂	1.19 ± 0.16	1390 ± 56	1168
104a	3β,2β, 6-OH 4′-Me	215^ɑ	-	-
104b	3β,2α, 6-OH 4′-Me	15310^ɑ	-	-
104c	3α,2β, 6-OH 4′-Me	930^ɑ	-	-
104d	3α,2α, 6-OH 4′-Me	7860^ɑ	-	-

^ɑIC₅₀ value for displacement of [H³]mazindol. IC₅₀ for cocaine 288 nM for displacement of [H³]mazindol

3-butyl 6/7 substituted

6/7-Substituted 3-butyl-phenyltropanes^[1]
Compound # (S. Singh)	Substituent	K_i nM displacement of [H³]mazindol binding	K_i nM [H³]DA uptake	Selectivity uptake/binding
Cocaine	H	270 ± 0.03	400 ± 20	1.5
121a	7β-CN	2020 ± 10	710 ± 40	0.3
121b	6β-CN	3040 ± 480	6030 ± 880	2.0
121c	7β-SO₂Ph	4010 ± 310	8280 ± 1340	2.1
121d	6β-SO₂Ph	4450 ± 430	8270 ± 690	1.8
121e	7α-OH	830 ± 40	780 ± 60	0.9
121f	H	100 ± 10	61 ± 10	0.6
121g	7β-CN	24000 ± 3420	32100 ± 8540	1.3
121h	6β-CN	11300 ± 1540	26600 ± 3330	2.3
121i	7β-SO₂Ph	7690 ± 2770	7050 ± 450	0.9
121j	6β-SO₂Ph	4190 ± 700	8590 ± 1360	2.0
121k	7α-SO₂Ph	3420 ± 1100	-	-
121l	7β-SO₂Ph, 7α-F	840 ± 260	2520 ± 290	3.0
121m	7α-F	200 ± 10	680 ± 10	3.4
121n	7β-F	500 ± 10	550 ± 140	1.1

intermediate 6- & 7-position synthesis modified phenyltropanes

6/7-synthetic intermediates^[1]
Compound # (S. Singh)	Substituent W	Substituent X	Substituent Y	Substituent Z

(±)-122a	CN	H	H	H
(±)-122b	H	H	CH	H
(±)-122c	H	CH	H	H
(±)-122d	H	H	H	CH
(±)-122e	SO₂Ph	H	H	H
(±)-122f	H	H	SO₂Ph	H
(±)-122g	H	SO₂Ph	H	H
(±)-122h	SO₂Ph	F	H	H
(±)-122i	F	SO₂Ph	H	H
(±)-122j	H	H	SO₂Ph	F

8-tropane (bridgehead) position modified

Nortropanes (N-demethylated)

NS2359 (GSK-372,475)

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.^[24] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.^[25]

Selected ββ Nortropanes
Code (S.S. #)	X para ^{(unless position otherwise given inline)}	DA	5HT	NE
RTI-142 75b	F	4.39	68.6	18.8
RTI-98 75d Nor^ɑ-RTI-55	I	0.69	0.36	11.0
RTI-110 75c	Cl	0.62	4.13	5.45
RTI-173 75f	Et	49.9	8.13	122
RTI-279 Nor^ɑ-RTI-280	para-Me meta-I	5.98 ± 0.48	1.06 ± 0.10	74.3 ± 3.8
RTI-305	Ethynyl	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0
RTI-307 Nor^ɑ-11z	Propynyl	6.11 ± 0.67	3.16 ± 0.33	115.6 ± 5.1
RTI-309 Nor^ɑ-11t	Vinyl	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18
RTI-330 Nor^ɑ-11s	Isopropyl	310.2 ± 21	15.1 ± 0.97	—
RTI-353	para-Et meta-I	330.54 ± 17.12	0.69 ± 0.07	148.4 ± 9.15

^ɑThe N-demethylated variant of (i.e. compound code-name after dash)

N-demethylating various β,β p-HC-phenyltropanes
N-Me compound code # → N-demethylated derivative compound code #	para-X	[³H]Paroxetine	[³H]WIN 35,428	[³H]Nisoxetine
11g→75f	Ethyl	28.4 → 8.13	55 → 49.9	4,029 → 122
11t→75i	vinyl	9.5 → 2.25	1.24 → 1.73	78 → 14.9
11y→75n	Ethynyl	4.4 → 1.59	1.2 → 1.24	83.2 → 21.8
11r→75g	1-Propyl	70.4 → 26	68.5 → 212	3,920 → 532
11v→75k	trans-propenyl	11.4 → 1.3	5.29 → 28.6	1,590 → 54
11w→75l	cis-propenyl	7.09 → 1.15	15 → 31.6	2,800 → 147
11x→75m	Allyl	28.4 → 6.2	32.8 → 56.5	2,480 → 89.7
11z→75o	1-Propynyl	15.7 → 3.16	2.37 → 6.11	820 → 116
11s→75h	i-Propyl	191 → 15.1	597 → 310	75,000 → ?
11u→75j	2-Propenyl	3.13 → 0.6	14.4 → 23	1,330? → 144

N-Demethylating phenyltropanes to find a NRI
Isomer	4′	3′	NE	DA	5HT
β,β	Me	H	60 → 7.2	1.7 → 0.84	240 → 135
β,β	F	H	835 → 18.8	15.7 → 4.4	760 → 68.6
β,β	Cl	H	37 → 5.45	1.12 → 0.62	45 → 4.13
β,α	Me	H	270 → 9	10.2 → 33.6	4250 → 500
β,α	F	H	1200 → 9.8	21 → 32.6	5060 → 92.4
β,α	Cl	H	60 → 5.41	2.4 → 3.1	998 → 53.3
β,α	F	Me	148 → 4.23	13.7 → 9.38	1161 → 69.8
β,α	Me	F	44.7 → 0.86	7.38 → 9	1150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).^[26]

N-norphenyltropanes^[1]
Short Name (S. Singh)	Para-X	DAT [³H]WIN 35428 IC₅₀ (nM)	5-HTT [³H]Paroxetine IC₅₀ (nM)	NET [³H]Nisoxetine IC₅₀ (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
Norcocaine	H	206 ± 29	127 ± 13	139 ± 9	0.6	0.7
75a	H	30.8 ± 2.3	156 ± 8	84.5 ± 7.5	5.1	2.7
75b	F	4.39 ± 0.20	68.6 ± 2.0	18.8 ± 0.7	15.6	4.3
75c	Cl	0.62 ± 0.09	4.13 ± 0.62	5.45 ± 0.21	6.7	8.8
75d	I	0.69 ± 0.2	0.36 ± 0.05	7.54 ± 3.19	0.5	10.9
75e	para-I & 2β-CO₂CH(CH₃)₂	1.06 ± 0.12	3.59 ± 0.27	132 ± 5	3.4	124
75f	C₂H₅	49.9 ± 7.3	8.13 ± 0.30	122 ± 12	0.2	2.4
75g	n-C₃H₇	212 ± 17	26 ± 1.3	532 ± 8.1	0.1	2.5
75h	CH(CH₃)₂	310 ± 21	15.1 ± 0.97	-	0.05	-
75i	CH=CH₂	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18	1.3	8.6
75j	C-CH₃ ║ CH₂	23 ± 0.9	0.6 ± 0.06	144 ± 12	0.03	6.3
75k	trans-CH=CHCH₃	28.6 ± 3.1	1.3 ± 0.1	54 ± 16	0.04	1.9
75l	cis-CH=CHCH₃	31.6 ± 2.2	1.15 ± 0.1	147 ± 4.3	0.04	4.6
75m	CH₂CH=CH₂	56.5 ± 56	6.2 ± 0.3	89.7 ± 9.6	0.1	1.6
75n	CH≡CH	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0	1.3	17.6
75o	CH≡CCH₃	6.11 ± 0.67	3.16 ± 0.33	116 ± 5.1	0.5	19.0
75p^ɑ	3,4-Cl₂	0.66 ± 0.24	1.4^b	-	2.1	-

^ɑThese values determined in Cynomolgus monkey caudate-putamen ^bThe radioligand used for 5-HTT was [³H]citalopram

2β-Propanoyl-N-norphenyltropanes^[1]
Short Name (S. Singh)	DAT [¹²⁵I]RTI-55 IC₅₀ (nM)	5-HTT [³H]Paroxetine K_i (nM)	NET [³H]Nisoxetine K_i (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
79a	0.07 ± 0.01	0.22 ± 0.16	2.0 ± 0.09	3.1	28.6
79b	4.7 ± 0.58	19 ± 1.4	5.5 ± 2.0	4.0	1.2
79c	380 ± 110	5.3 ± 1.0	3400 ± 270	0.01	8.9
79d	190 ± 17	150 ± 50	5100 ± 220	0.8	26.8
79e	490 ± 120	85 ± 16	4300 ± 1100	0.1	8.8
79f	1.5 ± 1.1	0.32 ± 0.06	10.9 ± 1.5	0.2	7.3
79g	16 ± 4.9	0.11 ± 0.02	94 ± 18	0.07	5.9

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies^[1]
Short Name (S. Singh)	Stereochemistry	DAT [³H]WIN 35428 IC₅₀ (nM)	5-HTT [³H]Paroxetine IC₅₀ (nM)	NET [³H]Nisoxetine IC₅₀ (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
Paroxetine	-	623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
R-81a	2β,3β	835 ± 90	480 ± 21	37400 ± 1400	0.6	44.8
R-81b	2α,3β	142 ± 13	90 ± 3.4	2500 ± 250	0.6	17.6
R-81c	2β,3α	3.86 ± 0.2	5.62 ± 0.2	14.4 ± 1.3	1.4	3.7
S-81d	2β,3β	1210 ± 33	424 ± 15	17300 ± 1800	0.3	14.3
S-81e	2α,3β	27.6 ± 2.4	55.8 ± 5.73	1690 ± 150	2.0	61.2
S-81f	2β,3α	407 ± 33	19 ± 1.8	1990 ± 176	0.05	4.9

N-replaced (S,O,C)

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Compound	X	2 Group	config	8	DA	5-HT	NE
Tropoxane	Cl,Cl	CO₂Me	(racemic) β,β	O	3.3	6.5	No data
O-4210^[27]	p-F	3-methyl-5-isoxazole	β,β	S	7.0	>1000	No data

8-Oxanortropanes, binding inhibition using monkey caudate-putamen^[1]
Compound # (S. Singh)	Para- (meta-)	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram	Selectivity 5-HTT/DAT
R/S-90a	H	>1000	>1000	-
R/S-90b	F	546	2580	4.7
R/S-90c	Cl	10	107	10.7
R/S-90d	Br	22	30	1.4
R/S-90e	I	7	12	1.7
R/S-90f	3,4-Cl₂	3.35	6.52	1.9
R-90g	3,4-Cl₂	3.27	4.67	1.4
S-90h	3,4-Cl₂	47	58	1.2
R/S-91a	H	1990	11440	5.7
R/S-91b	F	>1000	>10000	-
R/S-91c	Cl	28.5	816	28.6
R/S-91d	Br	9	276	30.7
R/S-91e	I	42	72	1.7
R/S-91f	3,4-Cl₂	3.08	64.5	20.9
R-91g	3,4-Cl₂	2.34	31	13.2
S-91h	3,4-Cl₂	56	2860	51.1

N-alkyl

Compound	X	2 Group	config	8	DAT	SERT	NET
FP-β-CPPIT	Cl	3′-phenylisoxazol-5′-yl	β,β	NCH₂CH₂CH₂F	-	-	-
FE-β-CPPIT	Cl	(3′-phenylisoxazol-5′-yl)	β,β	NCH₂CH₂F	-	-	-
Altropane (IACFT)	F	CO₂Me	β,β	NCH₂CH=CHF	-	-	-
RTI-310 U.S. Patent 5,736,123	I	CO₂Me	β,β	N-Prⁿ	1.17	-	-
RTI-311	I	CO₂Me	β,β	NCH₂CH=CH₂	1.79	-	-
RTI-312 U.S. Patent 5,736,123	I	CO₂Me	β,β	NBuⁿ	0.76	-	-
RTI-313 U.S. Patent 5,736,123	I	CO₂Me	β,β	NCH₂CH₂CH₂F	1.67	-	-
Ioflupane	¹²³I	CO₂Me	β,β	NCH₂CH₂CH₂F	-	-	-
RTI-251	Cl	CO₂Me	β,β	NCH₂CO₂Et	1.93	10.1	114
RTI-252	Cl	CO₂Me	β,β	NCH₂CH₂CO₂Et	2.56	35.2	125
RTI-242	Cl	β,β (bridged) -C(O)CH(CO₂Me)CH₂N			7.67	227	510

Bi- and tri-cyclic aza compounds and their uses U.S. Patent 6,150,376 WO 0007994

N-substituted 3β-phenylnortropanes^[1]
(including N-phthalimidoalkyl analogues of β-CIT)
Short Name (S. Singh)	Nitrogen side-chain (N8)	DAT [³H]GBR 12935 K_i (nM)	5-HTT [³H]Paroxetine K_i (nM)	NET [³H]Nisoxetine K_i (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
Cocaine	H	350 ± 80	>10000	>30000	>28.6	-
GBR 12909	0.06 ± 0.02	52.8 ± 4.4	>20000	880	-
WIN 35428 11b	H	14.7 ± 2.9	181 ± 21	635 ± 110	12.3	43.2
RTI-55 11e	H	1.40 ± 0.20	0.46 ± 0.06	2.80 ± 0.40	0.3	2

82a	CH₂CH=CH₂	22.6 ± 2.9^ɑ	-	-	-	-
82b	CH₂CH₂CH₃	43.0 ± 17.7^ɑ	-	-	-	-
82c	CH₂C₆H₅	58.9 ± 1.65^b	1073^c	-	18.2	-
82d	(CH₂)₃C₆H₅	1.4 ± 0.2^b	133 ± 7^c	-	95.0	-
82e	(CH₂)₅C₆H₅	3.4 ± 0.83^b	49.9 ± 10.2^c	-	14.7	-

83a	CH₂CH₂CH₂F	1.20 ± 0.29	48.7 ± 8.4	10000	40.6	8333
83b	CH₂CH₂F	4.40 ± 0.35	21.7 ± 8.3	>10000	4.9	-

84a	CH₂CH₂CH₂F	3.50 ± 0.39	0.110 ± 0.02	63.0 ± 4.0	0.03	18
84b	CH₂CH₂F	4.00 ± 0.73	0.140 ± 0.02	93.0 ± 17.0	0.03	23.2
84c	CH₂CHF₂	15.1 ± 3.7	9.6 ± 1.5	>5000	0.6	-
84d	CH₂CH₂CH₂Cl	3.10 ± 0.57	0.32 ± 0.06	96.0 ± 29.0	0.1	31.0
84e	CH₂CH₂CH₂Br	2.56 ± 0.57	0.35 ± 0.08	164 ± 47	0.1	64.1
84f	CH₂CH₂CH₂I	38.9 ± 6.3	8.84 ± 0.53	5000	0.2	128
84g	CH₂...methylcyclopropane	4.30 ± 0.87	1.30 ± 0.25	198 ± 9.6	0.3	46.0
84h	CH₂CH₂CH₂OH	5.39 ± 0.21	2.50 ± 0.20	217 ± 19	0.5	40.2
84i	CH₂CH₂(OCH₃)₂	6.80 ± 1.10	1.69 ± 0.09	110 ± 7.7	0.2	16.2
84j	CH₂CO₂CH₃	11.9 ± 1.4	0.81 ± 0.10	29.1 ± 1.0	0.07	2.4
84k	CH₂CON(CH₃)₂	12.2 ± 3.8	6.40 ± 1.70	522 ± 145	0.5	42.8
84l	CH₂CH₂CH₂OMs	36.3 ± 2.1	17.3 ± 1.2	5000	0.5	138
84m	COCH(CH₃)₂	2100 ± 140	102 ± 23	>10000	0.05	-
84n	(CH₂)₂Pht	4.23 ± 0.48	0.84 ± 0.02	441 ± 66.0	0.2	104
84o	(CH₂)₃Pht	9.10 ± 1.10	0.59 ± 0.07	74.0 ± 11.6	0.06	8.1
84p	(CH₂)₄Pht	2.38 ± 0.22	0.21 ± 0.02	190 ± 18.0	0.09	79.8
84q	(CH₂)₅Pht	2.40 ± 0.17	0.34 ± 0.03	60.0 ± 3.10	0.1	25.0
84r	(CH₂)₈Pht	2.98 ± 0.30	0.20 ± 0.02	75.0 ± 3.6	0.07	25.2
84s^d	CH₂CH=CH-CH₃	15 ± 1	75 ± 5	400 ± 80	5.0	26.7
84t^d	CH₂C(Br)=CH₂	30 ± 5	200 ± 40	>1000	6.7	-
84u^d	CH₂CH=CH₂I(E)	30 ± 5	960 ± 60	295 ± 33	32.0	9.8
84v^d	CH₂C≡CH	14 ± 1	100 ± 30	>1000	7.1	-
84w^d	CH₂C₆H₅	42 ± 12	100 ± 17	600 ± 100	2.4	14.3
84x^d	CH₂C₆H₄-2-CH₃	93 ± 19	225 ± 40	>1000	2.4	-

85a^d	para-H	113 ± 41	100 ± 20	>1000	0.9	-
85b^d	para-Cl, meta-Cl	29 ± 4	50 ± 6	500 ± 120	1.7	17.2
85c^d	para-Me	17 ± 7	500 ± 30	>1000	29.4	-
85d^d	para-CH(CH₃)₂	500 ± 120	450 ± 80	>1000	0.9	-
85e^d	para-n-C₃H₇	500 ± 100	300 ± 12	750 ± 160	0.6	1.5

^ɑIC₅₀ for displacement of [³H]cocaine. IC₅₀ for cocaine = 67.8 ± 8.7 (nM)
^bIC₅₀ values for displacement of [³H]WIN 35428
^cIC₅₀ values for displacement of [³H]citalopram
^dThe standard K_i value for the displacement of [³H]GBR 12935, [³H]paroxetine, and [³H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments

Tricyclic/N-constrained (inclu. N-bridged/fused/tethered)

3β-replaced (front-bridged phenyltropanes)

Constrained tropane:^[28]^[29]

Tricyclic tropanes^[30]

Compound	X	Y	R	SERT K_i (nM)	DAT K_i (nM)	NET K_i (nM)
1	Cl	Cl	CH₂OCOMe	1.6	1870	638
2	Br	Cl	CO₂Me	2.3	5420	459
3	I	Cl	CH₂OCOPh	0.06	>10K	>10K

p-methyl front & back bridged (phenyltropanes)

U.S. Patent 6,150,376

Structures mentioned in US6150376 table of K_i data.

Alternate 2D rendering of compound "42a" (from among the above 'bridged' phenyltropanes) to elucidate the potential overlaying structure of the place inhabited by the contrained nitrogen. Compare JNJ-7925476, tametraline and similar compounds.

RTI-242

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes *K_i* (nM)
Compound # (S. Singh's #)	2β=R	[³H]Mazindol binding	[³H]DA uptake	[³H]5-HT uptake	[³H]NE uptake	selectivity [³H]5-HT/[³H]DA
cocaine	CO₂CH₃	375 ± 68	423 ± 147	155 ± 40	83.3 ± 1.5	0.4
(–)-40 (–)-128		54.3 ± 10.2	60.3 ± 0.4	1.76 ± 0.23	5.24 ± 0.07	0.03
(+)-40 (+)-128		79 ± 19	114 ± 28	1.48 ± 0.07	4.62 ± 0.31	0.01
(±)-40 (±)-128		61.7 ± 8.5	60.3 ± 0.4	2.32 ± 0.23	2.69 ± 0.12	0.04
29β		620	1420	8030	—	—
30β		186	492	97.7	—	—
31β		47.0	211	28.5	—	—
29α		4140	20100	3920	—	—
30α		3960	8850	696	1150	—
45 129		6.86 ± 0.43	24.0 ± 1.3	1.77 ± 0.04	1.06 ± 0.03	0.07
42a 131a	n-Bu	4.00 ± 0.07	2.23 ± 0.12	14.0 ± 0.6	2.99 ± 0.17	6.3
41a 130a	n-Bu	17.2 ± 1.13	10.2 ± 1.4	78.9 ± 0.9	15.0 ± 0.4	7.8
42b 131b	Et	3.61 ± 0.43	11.3 ± 1.1	25.7 ± 4.3	4.43 ± 0.01	2.3
50a 133a	n-Bu	149 ± 6	149 ± 2	810 ± 80	51.7 ± 12	5.4
49a 132a	n-Bu	13.7 ± 0.8	14.2 ± 0.1	618 ± 87	3.84 ± 0.35	43.5
(–)-4		10500	16500	1890	70900	—
(+)-4		18500	27600	4630	38300	—
(–)-5		9740	9050	11900	4650	—
(+)-5		6770	10500	25100	4530	—
RTI-⁴²²⁹-242	N8/2β-C(O)CH(CO2Me)CH2N para-chloro	—	7.67 ± 0.31^ɑ	226.54 ± 27.37^b	510.1 ± 51.4^c	—

^ɑValue for displacement of [³H]WIN 35,428 binding @ DAT
^bValue for displacement of [³H]paroxetine binding to SERT
^cValue for displacement of [³H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4—5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130—133) preferred placement with DAT interaction.^[1] U.S. Patent 5,998,405

3,4-Cl₂ front-bridged phenyltropanes

Fused Tropane: NeuroSearch A/S, Scheel-Krüger et al. U.S. Patent 5,998,405

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0^4,8]- undecan-11 -one O-methyl-oxime	0.012	0.0020	0.0033
2	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.0^4,8]- undecan-11-one	0.18	0.035	0.0075
3	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime	0.0160	0.0009	0.0032
4	(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol	0.0750	0.0041	0.0028
5	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one	0.12	0.0052	0.0026
6	(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol	0.25	0.0074	0.0018
7	(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate	0.21	0.0061	0.0075
8	(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane	0.022	0.0014	0.0001

1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
2° amine is reacted with Br(CH₂)nCO₂Et.
Base used to abstract proton α- to CO₂Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

Remove N-Me
Add ɣ-bromo-chloropropane
Allow for cyclization with K₂CO₃ base and KI cat.

Cycloalkane-ring alterations of the tropane ring system

Azanonane (outer ring extended)

3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.^{[lower-alpha 7]} Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

[3.3.1]azanonane analogues
displacement of bound [³H]WIN 35428^[1]
Structure	Compound # (S. Singh)	K_i (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	146a	4600 ± 510
	146b	5730 ± 570
	146c	3450 ± 310
	146d	3470 ± 350
	147	13900 ± 2010

Azabornane (outer ring contracted)

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.^{[lower-alpha 8]}

2-exo-phenyl-7-azabicyclo[2.2.1]heptane:

The non-carboxylic (and DAT substrate, releasing agent) variant of exo-2-phenyl-7-azabicyclo(2.2.1)heptane-1-carboxylic acid (N.B. the carboxy in the latter shares the C1 tropane position with the two carbon nitrogen containing bridge; sharing in the leftmost (R) substitution of the above depiction & unlike the placement on the tropane for either the carbmethoxy or phenyl ring of the azabornane analogues given in this section)

With the carboxy ester function removed the resultant derived compound acts as a DAT substrate drug, thus an amphetaminergic releaser of MAT & VMAT, yet similar to phenyltropanes (that usually are only re-uptake ligands)^[31] cf. EXP-561 & BTQ.

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane.

[2.2.1]azabornane analogues
displacement of bound [³H]WIN 35428^[1]
Structure	Compound # (S. Singh)	K_i (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	155a	60,400 ± 4,800
	155b	96,500 ± 42
	155c	5,620 ± 390
	155d	18,900 ± 1,700

Piperidine homologues (inner two-carbon bridge excised)

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

p-chloro & related (piperidine homologues of phenyltropanes)

Phenyltropane piperidine analogues^[1]
Compound # (S. Singh)	X = para- / 4′- Substitution	R = 2-tropane position	DAT (IC₅₀ nM) [H³]WIN 35428 binding displacement	DA (IC₅₀ nM) [H³]DA uptake	Selectivity Uptake/Binding

Cocaine	H	CO₂Me	102 ± 9	239 ± 1	2.3

(±)-166a	Cl	β-CO₂CH₃	53.7 ± 1.9	37.8 ± 7.9	0.7
(-)-166a	Cl	β-CO₂CH₃	24.8 ± 1.6	85.2 ± 2.6	3.4
(+)-166a	Cl	β-CO₂CH₃	1360 ± 125	5090 ± 172	3.7

(-)-167a	Cl	β-CO₂OH	75.3 ± 6.2	49.0 ± 3.0	0.6
(+)-167a	Cl	β-CO₂OH	442 ± 32	—	—

(-)-168a	Cl	β-CO₂OAc	44.7 ± 10.5	62.9 ± 2.7	1.4
(+)-168a	Cl	β-CO₂OAc	928 ± 43	2023 ± 82	2.2

(-)-169a^[32]	Cl	β-n-Pr	3.0 ± 0.5	8.3 ± 0.6	2.8

(-)-170a	H	β-CO₂CH₃	769 ± 19	—	—

(±)-166b	Cl	α-CO₂CH₃	197 ± 8	—	—
(+)-166b	Cl	α-CO₂CH₃	57.3 ± 8.1	34.6 ± 3.2	0.6
(-)-166b	Cl	α-CO₂CH₃	653 ± 38	195 ± 8	0.3

(+)-167b	Cl	α-CO₂OH	240 ± 18	683 ± 47	2.8

(+)-168b	Cl	α-CO₂OAc	461 ± 11	—	—

(+)-169b	Cl	α-n-Pr	17.2 ± 0.5	23.2 ± 2.2	1.3

naphthyl & related (piperidine homologues of phenyltropanes)

Activity @ MAT for piperidine homologues of phenyltropanes, including naphthyl derivatives^[33]
Compound #	[H³]DA uptake (nM) IC₅₀	[H³]DA uptake (nM) Ki	[H³]NE uptake (nM) IC₅₀	[H³]NE uptake (nM) Ki	[H³]5-HTT uptake (nM) IC₅₀	[H³]5-HTT uptake (nM) Ki	Uptake Ratio DA/5-HT (Ki)	Uptake Ratio NE/5-HT (Ki)
Cocaine	459 ± 159	423 ± 147	127 ± 4.1	108 ± 3.5	168 ± 0.4	155 ± 0.4	2.7	0.69
Fluoxetine	>4500	>2500	193 ± 4.1	176 ± 3.5	8.1 ± 0.7	7.3 ± 0.7	624	24
20	75 ± 9.1	69 ± 8.1	101 ± 3.3	88 ± 2.9	440 ± 30	391 ± 27	0.18	0.23
6	23 ± 1.0	21 ± 0.9	-	34 ± 0.8	8.2 ± 0.3	7.6 ± 0.2	2.8	4.5
7	>1000	947 ± 135	-	241 ± 1.7	8.2 ± 0.3	7.6 ± 0.2	22.6	5.7
8	94 ± 9.6	87 ± 8.9	-	27 ± 1.6	209 ± 17	192 ± 16	0.45	0.14
9	293 ± 6.4	271 ± 5.9	-	38 ± 4.0	13 ± 0.7	12 ± 0.7	23	3.2
19	97 ± 8.6	90 ± 8.0	34 ± 2.5	30 ± 2.3	3.9 ± 0.5	3.5 ± 0.5	26	8.6
10	326 ± 1.2	304 ± 1.1	337 ± 37	281 ± 30	113 ± 4.3	101 ± 3.8	3.0	2.8
14	144 ± 20	131 ± 18	204 ± 5.6	175 ± 4.8	155 ± 3.9	138 ± 3.5	0.95	1.3
15	>1800	>1700	>1300	>1100	275 ± 39	255 ± 37	>6	>4
16	>1000	964 ± 100	>1200	>1000	334 ± 48	309 ± 44	3.1	3.5
17	213 ± 30	187 ± 26	399 ± 12	364 ± 9.2	189 ± 37	175 ± 34	1.1	2.1
18	184 ± 30	173 ± 26	239 ± 42	203 ± 36	67 ± 4.5	62 ± 4.1	2.8	3.3

Radiolabeled

Radiolabel Tropane:^[34] Page 64. G.A. Whitlock et al. Table 1 Potential SRI PET and SPECT ligands.

LBT-999, a radio-ligand.

Code	SERT K_i (nM)	NET K_i (nM)	DAT K_i (nM)	Radiolabel	In vivo study	Refs.
1	0.2	102.2	29.9	¹¹C	Non-human primate	^[35]
2	0.2	31.7	32.6	¹¹C	Non-human primate	^[36]
3	0.05	24	3.47	¹²³I	Rat	^[37]
4	0.08	28	13	¹⁸F	Non-human primate	^[38]
5	0.11	450	22	¹¹C	Rat, monkey	^[39]

IPT (N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with ¹²³I or ¹²⁵I and used as a ligand to map several MATs

Transition metal complexes

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC₅₀ of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites.^{[lower-alpha 9]}

"Transition metal" chelated phenyltropanes^[1]
Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	Configuration	DAT (IC₅₀ nM) displacement of [H³]WIN 35428	5-HTT (IC₅₀ nM) [H³]Citalopram	Selectivity 5-HTT/DAT
	WIN 35428	F	-	11.0 ± 1.0	160 ± 20	14.5
2β-chelated phenyltropanes
	73 TRODAT-1^ɑ	Cl	-	R=13.9, S=8.42^b	-	-
	74 TROTEC-1	F	-	high affinity site = 0.15 ± 0.04^c low affinity site = 20.3 ± 16.1^c	-	-
N-chelated phenyltropanes
	89a	F	2β	5.99 ± 0.81	124 ± 17	20.7
	89b	F	2α	2960 ± 157	5020 ± 1880	1.7
	89c	3,4-Cl₂	2β	37.2 ± 3.4	264 ± 16	7.1
	89d	Cl	-	0.31 ± 0.03^d	-	-

^ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1''R''-(''exo'', ''exo'')]-[99mTc]technetium
^bR- & S- isomer values are K_i (nM) for displacement of [¹²⁵I]IPT with technetium-99m replaced by rhenium
^cIC₅₀ (nM) values for displacement of [³H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC₅₀ for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
^dK_i value for displacement of [¹²⁵I]IPT radioligand.

Select annotations of above

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. Patent 6,329,520, U.S. Patent 7,011,813, U.S. Patent 6,531,483, and U.S. Patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Sister substances

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

References

Citations

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↑ Monoamine Transporter Binding Properties of 3β-(Substituted phenyl)tropane-2β-carboxylic Acid Methyl Esters
↑ 3β-(4-Methoxyphenyl)tropane-2β-carboxylic Acid Ester Analogs
↑ http://www3.interscience.wiley.com/journal/55001898/abstract
↑ Carroll, F. I.; Gray; Abraham; Kuzemko; Lewin; Boja; Kuhar (1993). "3-Aryl-2-(3′-substituted-1′,2′,4'-oxadiazol-5′-yl)tropane analogues of cocaine: affinities at the cocaine binding site at the dopamine, serotonin, and norepinephrine transporters". Journal of Medicinal Chemistry 36 (20): 2886–2890. doi:10.1021/jm00072a007. PMID 8411004.
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↑ Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
↑ Carroll, F.; Howard, J.; Howell, L.; Fox, B.; Kuhar, M. (2006). "Development of the dopamine transporter selective RTI-336 as a pharmacotherapy for cocaine abuse". The AAPS Journal 8 (1): E196–E203. doi:10.1208/aapsj080124. PMC 2751440. PMID 16584128.
↑ Carroll, F. I.; Gao; Abraham; Lewin; Lew; Patel; Boja; Kuhar (1992). "Probes for the cocaine receptor. Potentially irreversible ligands for the dopamine transporter". Journal of Medicinal Chemistry 35 (10): 1813–1817. doi:10.1021/jm00088a017. PMID 1588560.
↑ Wu; Reith, M.; Walker, Q.; Kuhn, C.; Carroll, F.; Garris, P. (2002). "Concurrent autoreceptor-mediated control of dopamine release and uptake during neurotransmission: an in vivo voltammetric study". Journal of Neuroscience 22 (14): 6272–6281. PMID 12122086.
↑ Xu, L.; Kulkarni, S. S.; Izenwasser, S.; Katz, J. L.; Kopajtic, T.; Lomenzo, S. A.; Newman, A. H.; Trudell, M. L. (2004). "Synthesis and Monoamine Transporter Binding of 2-(Diarylmethoxymethyl)-3β-aryltropane Derivatives". Journal of Medicinal Chemistry 47 (7): 1676–82. doi:10.1021/jm030430a. PMID 15027858.
↑ Hanna, Mona M. (2007). "Synthesis of some tropane derivatives of anticipated activity on the reuptake of norepinephrine and/or serotonin". Bioorganic 15 (24): 7765–7772. doi:10.1016/j.bmc.2007.08.055.
↑ Goodman, Mark M. (2003). "Synthesis and Characterization of Iodine-123 Labeled 2β-Carbomethoxy-3β-(4′-(( Z )-2-iodoethenyl)phenyl)nortropane. A Ligand for in Vivo Imaging of Serotonin Transporters by Single-Photon-Emission Tomography". Journal of Medicinal Chemistry 46 (6): 925–935. doi:10.1021/jm0100180. PMID 12620070.
↑ Blough, B.; Abraham, P.; Lewin, A.; Kuhar, M.; Boja, J.; Carroll, F. (1996). "Synthesis and transporter binding properties of 3β-(4′-alkyl-, 4′-alkenyl-, and 4′-alkynylphenyl)nortropane-2β-carboxylic acid methyl esters: serotonin transporter selective analogs". Journal of Medicinal Chemistry 39 (20): 4027–4035. doi:10.1021/jm960409s. PMID 8831768.
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↑ Carroll, F.; Tyagi, S.; Blough, B.; Kuhar, M.; Navarro, H. (2005). "Synthesis and monoamine transporter binding properties of 3alpha-(substituted phenyl)nortropane-2beta-carboxylic acid methyl esters. Norepinephrine transporter selective compounds". Journal of Medicinal Chemistry 48 (11): 3852–3857. doi:10.1021/jm058164j. PMID 15916437.
↑ Purushotham M, Sheri A, Pham-Huu DP, Madras BK, Janowsky A, Meltzer PC. The synthesis and biological evaluation of 2-(3-methyl or 3-phenylisoxazol-5-yl)-3-aryl-8-thiabicyclo[3.2.1]octanes. Bioorg Med Chem Lett. 2011 Jan 1;21(1):48-51. doi: 10.1016/j.bmcl.2010.11.076 PMID 21146984
↑ Hoepping, Alexander (2000). "Novel Conformationally Constrained Tropane Analogues by 6- e ndo-trig Radical Cyclization and Stille Coupling − Switch of Activity toward the Serotonin and/or Norepinephrine Transporter". Journal of Medicinal Chemistry 43 (10): 2064–2071. doi:10.1021/jm0001121. PMID 10821718.
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↑ exo-2-Phenyl-7-azabicyclo[2.2.1]heptane-1-carboxylic Acid: A New Constrained Proline Analogue. Source: Tetrahedron Letters, Volume 36, Number 39, 25 September 1995, pp. 7123-7126(4)
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↑ PMC 2671940

Im-pact indices (exact locations within sources cited) & foot-notations

↑ ^[1] ←Page #929 (5th page of article) § II
↑ Many of the RTI phenyltropanes are "RTI-4229-×××" where × is the specific phenyltropane code number.
―
e.g. RTI-55 is in-fact RTI-4229-55 but given below as simply RTI-55 for the sake of simplicity in shorthand (following as is done in the literature itself) as the subject matter in context is wholly within the scope of the phenyltropane coded category herein.
―
Worth mentioning in notation as to explain that other compounds entirely unrelated can be found with the same "RTI-×××" short-numbered assignation. Therefore it is to be expected that within different contexts a compound or chemical of the same name very possibly could be in reference to a entirely other substance of another chemical series non-analogous to those in this topic.
↑ ^[1] ←Page #970 (46th page of article) §B, 10th line
↑ ^[1] ←Page #971 (47th page of article) 1st ¶, 10th line
↑ ^[1] ←Page #940 (16th page of article) underneath Table 8., above §4
↑ ^[1] ←Page #941 (17th page of article) Figure 10
↑ ^[1] ←Page #967 (43rd page of article) 2nd column
↑ ^[1] ←Page #967 (43rd page of article) 2nd column
↑ ^[1] ←Page #955 (31st page of article) 1st (left) column, 2nd ¶

External links

Phenyltropanes (classifications)

2-Carboxymethyl Esters	Troparil WIN 35428 RTI-31 RTI-32 RTI-51 RTI-55 RTI-83

(3,4-Disubstituted Phenyl)-tropanes	Dichloropane RTI-112 RTI-353

Arylcarboxy	RTI-113 RTI-120

Carboxyalkyl	RTI-121 RTI-150

Acyl	PTT/WF-11 WF-23 PIT/WF-21 WF-33

β,α Stereochemistry	RTI-352 RTI-274

α,β Stereochemistry	Brasofensine Tesofensine NS2359

Heterocycles: 3-Substituted-isoxazol-5-yl	RTI-177 RTI-336 RTI-371

Heterocycles: 3-Substituted-1,2,4-oxadiazole	RTI-126 RTI-371

N-alkyl	FP-β-CPPIT FE-β-CPPIT Altropane Ioflupane (¹²³I)

N-replaced (S,O,C)	Tropoxane

Irreversible	RTI-76

Nortropanes (N-demethylated)	NS2359 (GSK-372,475)

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