title: Probes for narcotic receptor mediated phenomena. 44. Synthesis of an N-substituted 4-hydroxy-5-(3-hydroxyphenyl)morphan with high affinity and selective μ-antagonist activity.
abstract: A simple three-step synthesis of 5-(3-hydroxyphenyl)-2-methyl-2-azabicyclo[3.3.1]nonan-4-ol (3a) was achieved using an osmium tetroxide mediated oxidation of the known intermediate 6. A pyrrolidine-ring variant of 3a (3-(7-(hydroxymethyl)-6-methyl-6-azabicyclo[3.2.1]octan-1-yl)phenol (5)) was isolated when other routes were used. The epimeric hydroxy analogue 4a was synthesized by simple inversion of the stereochemistry at C-4. Both N-methyl (3a and 4a) and N-phenethyl (3b and 4b) derivatives were synthesized. The compounds were examined for their opioid receptor affinity and the N-phenethyl analogue 3b was found to have relatively weak affinity for the μ-opioid receptor (K(i) = 74 nM). However, the N-phenethyl analogue of the C-4 epimer, 4b, had about 15 fold higher affinity than 3b and was selective for the μ-opioid receptor (K(i) = 4.6 nM). Compound 4b was a moderately potent μ-opioid antagonist (K(e) = 12 nM), as determined by [(35)S]GTP-γ-S assays. Compounds 3b and 4b were energy minimized at the level of B3LYP/6-31G*, and then overlaid onto the 5-phenylmorphan, the (1R,5R,9S)-(-)-enantiomer of 2b (Fig. 1) with the α or β-OH group at the C-9 position. The spatial orientation of the hydroxyl moiety in 3b, 4b, 2a, and 2b is proposed to be the structural requirement for high μ-opioid receptor binding affinity and their agonist or antagonist activity. The modest change in spatial position of the hydroxyl moiety, and not the N-substituent, induced the change from potent agonist to an antagonist of moderate potency.
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: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.forename: Yong Sok
authors.initials: YS
authors.lastname: Lee
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D015394:Molecular Structure; D009019:Morphinans / Q000737:chemistry*; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D011957:Receptors, Opioid / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C573621:5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo(3.3.1)nonan-4-ol; D053961:Azabicyclo Compounds; D009019:Morphinans; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C042531:phenylmorphan