Probes for narcotic receptor mediated phenomena. 41. Unusual inverse μ-agonists and potent μ-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans.
Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher μ-affinity than the compound with an N-phenylpropyl substituent (K(i) = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [(35)S]GTP-γ-S functional binding assay using nondependent cells that stably express the cloned human μ-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent μ-opioid antagonists ((+)-29, K(e) = 0.17 and (-)-30, K(e) =0.3) in the [(35)S]GTP-γ-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their μ-opioid receptor affinity in terms of the spatial position of N-substituents.
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, Maryland 20892-9415, United States.
Kejun
K
Cheng
Yong Sok
YS
Lee
Richard B
RB
Rothman
Christina M
CM
Dersch
Ross W
RW
Bittman
Arthur E
AE
Jacobson
Kenner C
KC
Rice
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003521:Cyclopropanes; D009019:Morphinans; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
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