title: Probes for narcotic receptor mediated phenomena. 48. C7- and C8-substituted 5-phenylmorphan opioids from diastereoselective alkylation.
abstract: The exploration of the effect of substituents at C7 and C8 of the 5-phenylmorphans on their affinity for opioid receptors was enabled by our recently introduced "one pot" diastereoselective synthesis that provided C7-oxo, hydroxy and alkyl substituents, C8-alkyl substituted 5-phenylmorphans, and compounds that had a new cyclohexane ring that includes the C7 and C8 carbon atoms of the 5-phenylmorphan. The affinity of the 5-phenylmorphans for opioid receptors is increased by a C8-methyl substituent, compared with its C7 analog. The affinity of the newly synthesized compounds is generally for the μ-opioid receptor, rather than the δ- or κ-receptors. Addition of a new cyclohexane ring to the C7 and C8 positions on the cyclohexane ring of the 5-phenylmorphans enhances μ-receptor affinity, bringing the Ki to the subnanomolar level. Unexpectedly, the N-methyl substituted compounds generally had higher affinity than comparable N-phenethyl-substituted relatives. The configurations of two compounds were determined by single-crystal X-ray crystallographic analyses.
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, MD 20892-9415, USA.
authors.forename: Hwan Jung
authors.initials: HJ
authors.lastname: Lim
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000478:Alkylation; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009019:Morphinans; D011957:Receptors, Opioid; C042531:phenylmorphan
keywords: C7- and C8-substituted 5-phenylmorphans; Opioid receptor affinity; “One-pot” diastereoselective synthesis