The crystal structure and molecular conformation of threo 5-methylmetadone in relation to opioid receptor binding

W. L. Duax, G. D. Smith, J. F. Griffin, P. D. Strong, P. S. Portoghese

Research output: Contribution to journalArticlepeer-review

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Abstract

Crystals of the hydrochloride salt of the biologically inactive threo isomer of 5-methylmethadone, C22H30ONCl, are monoclinic space group P21 with unit cell dimnsionsa = 11.019 Å, b = 8.6153Å, c = 10.680Å and β = 93.026°. The observed conformation is one in which the nitrogen bearing chain is extended with the substituents on C(5) and C(6) nearly eclipsed, a feature compatible with NMR studies and molecular mechanics calculations. The very potent agonist (5S, 6S)-erythro-5-methylmethadone has a solid state conformation in which the N atom is rotated back toward the phenyl rings [C(4)-C(5)-C(6)-N = 97°]in agreement with molecular mechanics calculations. The fact that the more potent enantiomers, (6R)-methadone and (5S)-isomethadone, and the inactive threo isomer are observed in the extended solid state conformation in contrast to (5S, 6S)-erythro-5-methylmethadone is consistent with three different models for their interaction with opioid receptors. It is proposed that the more likely of these involves a receptor bound conformation of (6R)-methadone and (5S)-isomethadone that resembles the conformation of (5S, 6S)-erythro-5-methylmethadone or that opioid receptors recognize both gauche-like and extended conformations.

Original languageEnglish (US)
Pages (from-to)467-471
Number of pages5
JournalTetrahedron
Volume40
Issue number3
DOIs
StatePublished - 1984

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