Absolute configuration and conformation of the pure opioid antagonist (+)-2,9 alpha-dimethyl-5-(m-hydroxyphenyl)morphan.
(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.
Froimowitz
M
M
Alcohol and Drug Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178-9106.
Pangborn
W
W
Cody
V
V
D055598:Chemical Phenomena; D002627:Chemistry, Physical; D008956:Models, Chemical; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D014961:X-Ray Diffraction
D009019:Morphinans; D009292:Narcotic Antagonists; C040990:2,9-dimethyl-5-(3-hydroxyphenyl)morphan