Naltrindole

Naltrindole

Systematic (IUPAC) name
17-Cyclopropylmethyl-6,7-dehydro-4,5-epoxy -3,14-dihydroxy-6,7,2',3'-indolomorphinan
Clinical data
Routes of administration	IV
Identifiers
CAS Number	111555-53-4
ATC code	none
PubChem	CID 5497186
IUPHAR/BPS	1641
ChemSpider	4593753
ChEMBL	CHEMBL567175
Chemical data
Formula	C26H26N2O3
Molar mass	414.496 g/mol
SMILES Oc4c3O[C@H]7c2c(c1ccccc1n2)C[C@@]6(O)[C@H]5N(CC[C@@]67c3c(cc4)C5)CC8CC8
InChI InChI=1S/C26H26N2O3/c29-19-8-7-15-11-20-26(30)12-17-16-3-1-2-4-18(16)27-22(17)24-25(26,21(15)23(19)31-24)9-10-28(20)13-14-5-6-14/h1-4,7-8,14,20,24,27,29-30H,5-6,9-13H2/t20-,24+,25+,26-/m1/s1 Key:WIYUZYBFCWCCQJ-IFKAHUTRSA-N
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Naltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research. In May 2012 a paper was published in Nature with the structure of naltrindole in complex with the mouse δ-opioid G-protein coupled receptor, solved by X-ray crystallography.^[1]

Drug design

Since peptide compounds are unable to cross the blood–brain barrier, researchers developed naltrindole to be a non-peptide antagonist analog of the delta-preferring endogenous opiate enkephalin. Enkephalin contains an aromatic phenyl group on its Phe⁴ residue, which was hypothesized to be the "address" sequence responsible for the opiate's delta opioid receptor affinity.^[2] Thus, attachment of a phenyl-containing indole molecule to the C-ring of naltrexone's morphinan base successfully produced a drug with the high receptor affinity of naltrexone, but which binds almost exclusively to the delta opioid receptor.^[3]

References

1. Granier, S.; Manglik, A.; Kruse, A. C.; Kobilka, T. S.; Thian, F. S.; Weis, W. I.; Kobilka, B. K. (2012). "Structure of the δ-opioid receptor bound to naltrindole". Nature 485 (7398): 400–404. doi:10.1038/nature11111. PMC 3523198. PMID 22596164.
2. Lipkowski, AW; Tam, SW; Portoghese, PS (Jul 1986). "Peptides as receptor selectivity modulators of opiate pharmacophores". Journal of Medicinal Chemistry 29 (7): 1222–5. doi:10.1021/jm00157a018. PMID 2879914.
3. Portoghese, PS; Sultana, M; Takemori, AE (Jan 1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". European Journal of Pharmacology 146 (1): 185–6. doi:10.1016/0014-2999(88)90502-X. PMID 2832195.