Probes for Narcotic Receptor Mediated Phenomena. Part 28: New Opioid Antagonists from Enantiomeric Analogues of 5-(3-Hydroxyphenyl)- N-phenylethylmorphan

• Published in: Bioorganic & medicinal chemistry 2002-10, Vol.10 (10), p.3319-3329
• Main Authors: Hashimoto, Akihiro, Jacobson, Arthur E, Rothman, Richard B, Dersch, Christina M, George, Clifford, Flippen-Anderson, Judith L, Rice, Kenner C
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Crystallography, X-Ray; Guinea Pigs; Medical sciences; Molecular Probes - chemical synthesis; Molecular Probes - pharmacokinetics; Molecular Structure; Morphinans - chemical synthesis; Morphinans - pharmacokinetics; Narcotic Antagonists - chemical synthesis; Narcotic Antagonists - pharmacokinetics; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Receptors, Opioid - metabolism; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(02)00219-5

Enantiomeric analogues of 5-(3-hydroxyphenyl)morphan ligands were synthesized and evaluated because of our unexpected finding that opioid antagonists can be obtained in the 5-phenylmorphan series of opioids without sterically hindering the rotation of the phenolic ring. We determined the opioid receptor binding affinity of these new analogues, as well as the efficacy of the more interesting ligands. One of the new compounds [(1 R,5 S)-(−)-3-[2-(3′-phenylpropyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 15] was found to have half of the efficacy of naloxone, a potent opioid antagonist, in the [ 35S]GTPγS assay, and two others (1 R,5 S)-(−)-3-[2-(4′-phenylbutyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 17, and (1 R,5 S,1′ S)-(+)-3-[2-(1′-methyl-2′-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol, 26, acted as moderately potent opioid antagonists. X-ray crystallographic structure data were obtained on three compounds. Two of them had three chiral centers; 25 [(1 R,5 S,1′ R)-(−)-3-[2-(1′-methyl-2′-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol] was determined to have the 1 R,5 S,1′ R configuration, and 26 the 1 R,5 S,1′ S configuration. Since (1 S,5 R)-(+)-2-bromo-5-[2-(2′-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol ( 32) was a position isomer of (1 S,5 R)-(+)-4-bromo-3-[2-(2′-phenylethyl)-2-azabicyclo[3.3.1]non-5-yl]-phenol ( 30), and both showed the same 1H NMR spectrum, the structure of 32 was unequivocally determined by X-ray structure analysis. Graphic