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 language | English (US) |
---|---|
Pages (from-to) | 467-471 |
Number of pages | 5 |
Journal | Tetrahedron |
Volume | 40 |
Issue number | 3 |
DOIs | |
State | Published - 1984 |
Bibliographical note
Funding Information:Acknowledgements-Research supportedi n part by Grant No. RR-05716f rom the Division of ResearchR esources, DHHS and by a grant from the Margaret L. Wendt Foundation. The authorsw ish to expressth eir appreciationto Dr. W. C. Groutas for the crystallization of fhreo-5-methylmethadonaen d for the technicaal ssistanceof Elaine DeJamette,D r. Dale Swenson,a nd the draftinga nd secretarial staffs.