List of methylphenidate analogues

3D molecular rendering of methylphenidate (MPH)

3D molecular rendering of ethylphenidate (EPH)

This is a list of methylphenidate (MPH or MPD) analogues. Regular methylphenidate can come in several varieties. Including: the racemate, the enantiopure (dextro or levo) of its stereoisomers; erythro or threo (either + or -) among its diastereoisomers & lastly the isomers S,S; S,R/R,S or R,R. The variant with optimized efficacy is not the usually attested generic or common pharmaceutical brands (e.g. Ritalin, Daytrana etc.) but the (R,R)-dextro-(+)-threo, which has a binding profile on par with or better than that of cocaine.^{[lower-alpha 1]} (Note however the measure of five fold (5×) discrepancy in the entropy of binding at their presumed shared target binding site, which may account for the higher abuse potential of cocaine over methylphenidate despite affinity for associating; i.e the latter dissociates more readily once bound despite efficacy for binding).^{[lower-alpha 2]}

Also of note is that methylphenidate in demethylated form is acidic; a conformation known as ritalinic acid.^[2] This gives the potential to yield a conjugate salt^[3] form effectively protonated by a salt nearly chemically duplicate/identical to its own structure; creating a "methylphenidate ritalinate".^[4]

The carboxymethyl (methyl acetate) has sometimes been replaced with similar length ketones to increase duration. For instance, the methoxycarbonyl has had examples of having been replaced with an alkyl group (such as Kozikowski showed with RTI-31 n-propyl residue. cf.^[5])

Desoxypipradrol (and thus Pipradrol, including such derivatives as AL-1095, Diphemethoxidine, SCH-5472 & D2PM), and even mefloquine, 2-benzylpiperidine & rimiterol could be considered vaguely related structurally, with the former ones also functionally so, as loosely analogous compounds.

Enpiroline is one further example, loosely related by being based on the 2-benzylpiperidine skeleton, although in its case it is actually heteroaromatic; also of note are etoxadrol and dioxadrol.

Pethidine (Meperidine) is a loose structural analog (being rather between methylphenidate and certain piperidine phenyltropanes) which, though considered functionally an opioid, is also shown to have dopaminergic reuptake qualities.^[6]

Common (e.g. well established in literature et attested within grey market depositories) MPH analog compounds

• 

  Racemic methylphenidate

• 

  Enantiopure dextrorotatory
  ("D")methylphenidate
  (The stereochemistry on both carbons is dictated by 1 single wedge)
  e.g. Focalin

• 

  Transesterification product of MPH
  when exposed to ethanol in vivo

• 

  4-MeTMP

• 

  Propylphenidate

• 

  Dichloro-methylphenidate

• 

  Methylnaphthidate^{✲
  ✲}The aforementioned specific analogue page has an additional binding values table at its remote internal-link for multiple threo-methylphenidate analogues besides its own.

• 

  O-2172 The usual methylphenidate piperidine ring has been replaced by a cyclopentane (without the pyrrolidine nitrogen) and a di-chloro at the phenyl ring

• 

  Isopropylphenidate^[1]

• 

  Restricted Rotation Analog (RRA)
  of threo-methylphenidate.
  (cf. vabicaserin)

1. ^ Markowitz, J. S.; Zhu, H. J.; Patrick, K. S. (2013). "Isopropylphenidate: An Ester Homolog of Methylphenidate with Sustained and Selective Dopaminergic Activity and Reduced Drug Interaction Liability". Journal of Child and Adolescent Psychopharmacology 23 (10): 648–54. doi:10.1089/cap.2013.0074. PMID 24261661.

Staple permutations of ubiquitous simple substitution pattern arrangements of methylphenidate

The differing combinations of R/S-(+)- isomers of Ethylphenidate^* (EPH)

(R,R)-(+)- isomer ^{vide supra}

(R,S)-(+)- isomer ^{vide supra}

(S,R)-(+)- isomer ^{vide supra}

(S,S)-(+)- isomer ^{vide supra}

^*Aforementioned as possible "trans-esterification" product of MPH:
^{Note carboxy has ethyl (i.e. carbethoxy) rather than methyl (i.e. carbmethoxy)}

Aryl substitutions

Phenyl ring substituted methylphenidate analogues^{[lower-alpha 3]}

Compound	S. Singh's alphanumeric assignation (name)	R^1	R^2	IC50 (nM) (Inhibition of [^3H]WIN 35428 binding)	IC50 (nM) (Inhibition of [^3H]DA uptake)	Selectivity uptake/binding
	(D-threo-methylphenidate)	H, H		33	244 ± 142 (171 ± 10)	7.4
	(L-threo-methylphenidate)	540	5100 (1468 ± 112)	9.4
	(D/L-threo-methylphenidate) "eudismic ratio"	6.4	20.9 (8.6)	-
	(DL-threo-methylphenidate)	83.0 ± 7.9	224 ± 19	2.7
	(R-benzoyl-methylecgonine) (cocaine)	(H, H)		173 ± 13	404 ± 26	2.3
	351a	F	H y d r o g e n i.e. H	35.0 ± 3.0	142 ± 2.0	4.1
	351b	Cl		20.6 ± 3.4	73.8 ± 8.1	3.6
	351c	Br		6.9 ± 0.1	26.3 ± 5.8	3.8
	351d	(d) Br		-	22.5 ± 2.1	-
	351e	(l) Br		-	408 ± 17	-
	351d/e "eudismic ratio"	(d/l) Br		-	18.1	-
	351f	I		14.0 ± 0.1	64.5 ± 3.5	4.6
	351g	OH		98.0 ± 10	340 ± 70	3.5
	351h	OCH3		83 ± 11	293 ± 48	3.5
	351i	(d) OCH3		-	205 ± 10	-
	351j	(l) OCH3		-	3588 ± 310	-
	351i/j "eudismic ratio"	(d/l) OCH3		-	17.5	-
	351k	CH3		33.0 ± 1.2	126 ± 1	3.8
	351l	t-Bu		13500 ± 450	9350 ± 950	0.7
	351m	NH2.HCl		34.6 ± 4.0	115 ± 10	3.3
	351n	NO2		494 ± 33	1610 ± 210	3.3
	352a	F		40.5 ± 4.5	160 ± 0.00	4.0
	352b	Cl		5.1 ± 1.6	23.0 ± 3.0	4.5
	352c	Br		4.2 ± 0.2	12.8 ± 0.20	3.1
	352d	OH		321 ± 1.0	790 ± 30	2.5
	352e	OMe		288 ± 53	635 ± 35	0.2
	352f	Me		21.4 ± 1.1	100 ± 18	4.7
	352g	NH2.HCl		265 ± 5	578 ± 160	2.2
	353a	2′-F		1420 ± 120	2900 ± 300	2.1
	353b	2′-Cl		1950 ± 230	2660 ± 140	1.4
	353c	2′-Br		1870 ± 135	3410 ± 290	1.8
	353d	2′-OH		23100 ± 50	35,800 ± 800	1.6
	353e	2′-OCH3		101,000 ± 10,000	81,000 ± 2000	0.8
	354a	Cl, Cl (3′,4′-Cl2)		5.3 ± 0.7	7.0 ± 0.6	1.3
	354b	I	OH	42 ± 21	195 ± 197	4.6
	354c	OMe, OMe (3′,4′-OMe2)		810 ± 10	1760 ± 160	2.2

Piperidin-2-yl(thiophen-2-yl)methanone or cyclomethiodrone (TCAT), an empathogen methylphenidate analogue.

Both analogues 374 & 375 displayed higher potency than methylphenidate at DAT. In further comparison, 375 (the 2-naphthyl) was additionally two & a half times more potent than 374 (the 1-naphthyl isomer).^{[lower-alpha 4]}

Pentedrone is a structure similar to the above TCAT, yet is an intermediate between the methylphenidate class and that of the substituted cathinones.

e.g. out from among such examples, the differentiating factor is that the ring formation is left open ("opened" with the excess bond not fused, as above, or omitting one or more bonds on the ring: such as is the case with MABP) in the non-MPH compared analogues.

Aryl exchanged analogues

Phenyl ring modified methylphenidate analogues^{[lower-alpha 5]}

Compound	S. Singh's alphanumeric assignation (name)	Ring	Ki (nM) (Inhibition of [^125I]IPT binding)	Ki (nM) (Inhibition of [^3H]DA uptake)	Selectivity uptake/binding
	(D-threo-methylphenidate)	benzene	324	-	-
	(DL-threo-methylphenidate)		82 ± 77	429 ± 88	0.7
	374	1-naphthalene	194 ± 15	1981 ± 443	10.2
	375 (HDMP-28)	2-naphthalene	79.5	85.2 ± 25	1.0
	376	benzyl	>5000	-	-

HDMP-29, a manifold (multiple augmented) analogue of both the phenyl (to a 2-naphthalene) and piperidine (to a 2-pyrrolidine) rings.^[7]

Piperidine nitrogen methylated phenyl-substituted variants

N-methyl phenyl ring substituted methylphenidate analogues^{[lower-alpha 6]}

Compound	S. Singh's alphanumeric assignation (name)	R	IC50 (nM) (Inhibition of binding at DAT)
	373a	H	500 ± 25
	373b	4″-OH	1220 ± 140
	373c	4″-CH3	139 ± 13
	373d	3″-Cl	161 ± 18
	373e	3″-Me	108 ± 16

HDEP-28, Ethylnaphthidate.

Cycloalkane extensions, contractions & modified derivatives

Piperidine ring modified methylphenidate analogues^{[lower-alpha 7]}

Compound	S. Singh's alphanumeric assignation (name)	Cycloalkane ring	Ki (nM) (Inhibition of binding)
	380	2-pyrrolidine (cyclopentane)	1336 ± 108
	381	2-azepane (cycloheptane)	1765 ± 113
	382	2-azocane (cyclooctane)	3321 ± 551
	383	4-1,3-oxazinane (cyclohexane)	6689 ± 1348

Methyl 2-(1,2-oxazinan-3-yl)-2-phenylacetate

Methyl 2-(1,3-oxazinan-2-yl)-2-phenylacetate

☝The two other (in addition to compound 383) potential oxazinane methylphenidate analogues.

Methyl 2-phenyl-2-(morpholin-3-yl)acetate A.K.A. Methyl 2-morpholin-3-yl-2-phenylacetate

☜Methylmorphenate methylphenidate analogue.[8]

Alternate two dimensional rendering of "D-threo-methylphenidate"; demonstrating the plasticity of the piperidine ring in a 'flexed' or "chair" conformation. (the latter term can denote a structure containing a bridge in the ring when so-named, unlike the above).

N.B. although the cyclohexane conformation, if considering both the hydrogen on the plain bond and the implicit carbon on the dotted bond are not shown as positioned as would be for the least energy state inherent to what rules apply, internally, to the molecule in and of itself: possibility of movement between putative other ligand sites in suchwise, here regarding what circumstance allows for describing it as "flexed" thus mean it has shown tendency for change in situ depending on its environment and adjacent sites of potential interaction as against its least energy state.

Various MPH congener affinity values inclusive of norepinephrine & serotonin

Values for dl-threo-methylphenidate derivatives are the mean (s.d.)^[9] of 3—6 determinations, or are the mean of duplicate determinations. Values of other compounds are the mean—s.d. for 3—4 determinations where indicated, or are results of single experiments which agree with the literature. All binding experiments were done in triplicate.^[10]

Binding and uptake IC₅₀ (nM) values for MAT.

Compound	DA	DA Uptake	NE	5HT
Methylphenidate	84 ± 33	153 ± 92	514 ± 74	>50,000
o-Bromomethylphenidate	880 ± 316	—	20,000	—
m-Bromomethylphenidate	4 ± 1	18 ± 11	20 ± 6	3,800
p-Bromomethylphenidate	21 ± 3	45 ± 19	31 ± 7	2,600
p-Hydroxymethylphenidate	125	263 ± 74	270 ± 69	17,000
p-Methyloxymethylphenidate	42 ± 24	490 ± 270	410	11,000
p-Nitromethylphenidate	180	—	360	5,900
p-Iodomethylphenidate	26 ± 14	—	32	1,800^ɑ
m-Iodo-p-hydroxymethylphenidate	42 ± 21	195 ± 197	370 ± 64	5,900
N-Methylmethylphenidate	1,400	—	2,800	40,000
d-threo-Methylphenidate	33	—	244 ± 142	>50,000
l-threo-Methylphenidate	540	—	5,100	>50,000
dl-erythro-o-Bromomethylphenidate	10,000	—	50,000	—
Cocaine	120	313 ± 160	2,100	190
WIN 35,428	13	—	530	72
Nomifensine	29 ± 16	—	15 ± 2	1,300^ɑ
Mazindol	9 ± 5	—	3 ± 2	92
Desipramine	1,400	—	3.5	200
Fluoxetine	3,300	—	3,400	2.4

• ^ɑDenotes that preparation of membrane and results extrapolated therefrom originated from frozen tissue, which is known to change results when interpreting against fresh tissue experiments.

p-hydroxymethylphenidate displays low brain penetrability, ascribed to its phenolic hydroxyl group undergoing ionization at physiological pH.

Test environment conditioning & control studies

Temperature effect with Hill slope^[11][12][13] measurements on MPD binding IC₅₀ (nM) values for MAT.

Compound	0° (zero degrees)	0° (zero degrees) Hill slope^ɑ	22° (twenty-two degrees)	22° (twenty-two degrees) Hill slope^ɑ	36° (thirty-six degrees)	36° (thirty-six degrees) Hill slope^ɑ
Methylphenidate (MPH, MPD)	51 ± 24	0.99 ± 0.11	72 ± 29	0.90 ± 0.10	265 ± 175	0.70 ± 0.02
o-bromo-methylphenidate	1150 ± 83	0.97 ± 0.08	880 ± 316	0.79 ± 0.14	954 ± 190	0.88 ± 0.08

• ^ɑThe 'Hill' "slope" is a parameter for a biochemical equation named for Archibald Hill; 'degrees' in all cases refer to temperature, measurement of heat & cold, and not to angles. Thus "Hill slope" terminology herein has naught to do with effect of g-force or deviations of a level plane in the context of these values.

See also

HDMP-28 molecular model superimposed over β-CFT. cf. cocaine, and the phenyltropane class of drugs, including all subsets of related derivatives for either as pertaining in similarity to methylphenidate analogs.

• List of phenyltropanes
• List of cocaine analogues
• Substituted phenylmorpholines

External links

• "Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters." doi:10.1016/0024-3205(96)00052-5 Mirror hotlink
• "Azido-iodo-N-benzyl derivatives of threo-methylphenidate (Ritalin, Concerta): Rational design, synthesis, pharmacological evaluation, and dopamine transporter photoaffinity labeling." Bioorg Med Chem. 2011 Jan 1;19(1):504-12. doi: 10.1016/j.bmc.2010.11.002. Epub 2010 Nov 4.
• "Uses of methylphenidate derivatives" Google patents. Pub. # US 20060183773 A1
• Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter. J Med Chem. 2007 Jan 25;50(2):219-32.
• Synthesis of methylphenidate analogues and their binding affinities at dopamine and serotonin transport sites. doi:10.1016/j.bmcl.2003.12.097
• Vinylogous amide analogs of methylphenidate. Bioorg Med Chem Lett. 2005 Jun 15;15(12):3044-7.
• Biochemical and Behavioral Characterization of Novel Methylphenidate Analogs doi: 10.1124/jpet.301.2.527
• Methylphenidate analogs with behavioral differences interact differently with arginine residues on the dopamine transporter in rat striatum doi: 10.1002/syn.20161
• Quantitative structure-activity relationship studies of threo-methylphenidate analogs.
• Evolution of a Compact Photoprobe for the Dopamine Transporter Based on (±)-threo-Methylphenidate doi: 10.1021/ml3000098
• Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction European Journal of Medicinal Chemistry. Howard M Deutsch et al. Volume 36, Issue 4, April 2001, Pages 303–311

References

1. Satendra Singh et al. Chemistry, Design, and Structure-Activity Relationship of Cocaine Antagonists. Chem. Rev. 2000; 100. 925-1024 DOI: 10.1002/chin.200020238.Mirror hotlink.
2. Correlation between methylphenidate and ritalinic acid concentrations in oral fluid and plasma. Clin Chem. 2010 Apr;56(4):585-92. doi: 10.1373/clinchem.2009.138396. PMID 20167695
3. Process for the preparation of dexmethylphenidate hydrochloride Google patents; Publication #US 20040180928 A1
4. Resolution of ritalinic acid salt Google patents; Publication #US6441178 B2
5. Froimowitz, M.; Gu, Y.; Dakin, L.; Nagafuji, P.; Kelley, C.; Parrish, D.; Deschamps, J.; Janowsky, A. (2007). "Slow-onset, long-duration, alkyl analogues of methylphenidate with enhanced selectivity for the dopamine transporter". Journal of Medicinal Chemistry 50 (2): 219–232. doi:10.1021/jm0608614. PMID 17228864.
6. The cocaine-like behavioral effects of meperidine are mediated by activity at the dopamine transporter. Eur J Pharmacol. 1996 Feb 15;297(1-2):9-17. PMID 8851160
7. The Reinforcing Efficacy of Psychostimulants in Rhesus Monkeys: The Role of Pharmacokinetics and Pharmacodynamics 0022-3565/03/3071-356–366 The Journal Of Pharmacology And Experimental Therapeutics. Vol. 307, No. 1
8. U.S. National Library of Medicine, PubChem Compound Summary for CID 85054562
9. "Mean ± SEM" or "Mean (SD)"? Jaykaran. Indian J Pharmacol. 2010 Oct; 42(5): 329. doi: 10.4103/0253-7613.70402
10. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 1996;58(12):231-9. PMID 8786705
11. Hill coefficients, dose–response curves and allosteric mechanisms Heino Prinz. J Chem Biol. 2010 Mar; 3(1): 37–44. Published online 2009 Sep 25. doi: 10.1007/s12154-009-0029-3
12. Evaluation of Hill Slopes and Hill Coefficients when the Saturation Binding or Velocity is not Known Laszlo Endrenyi, Csaba Fajszi, F. H. F. Kwong., European Journal of Biochemistry (Impact Factor: 3.58). 03/1975; 51(2):317-28. DOI: 10.1111/j.1432-1033.1975.tb03931.x
13. Computational tools for fitting the Hill equation to dose–response curves Sudhindra R. Gadagkar (Department of Biomedical Sciences, College of Health Sciences, Midwestern University, Glendale, AZ 85308, USA), Gerald B. Call (Department of Pharmacology, Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ 85308, USA). doi:10.1016/j.vascn.2014.08.006

1. ^[1] ←Page #1,005 (81st page of article) §VI. Final ¶.
2. ^[1] ←Page #1,006 (82nd page of article) 2nd column, end of first ¶.
3. ^[1] ←Page #1,010 (86th page of article) Table 47, Page #1,007 (83rd page of article) Figure 52
4. ^[1] ←Page #1,010 (86th page of article) 2nd ¶, lines 2, 3 & 5.
5. ^[1] ←Page #1,010 (86th page of article) Table 49, Page #1,007 (83rd page of article) Figure 54
6. ^[1] ←Page #1,010 (86th page of article) Table 48, Page #1,007 (83rd page of article) Figure 53
7. ^[1] ←Page #1,011 (87th page of article) Table 50, Page #1,007 (83rd page of article) Figure 55