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Bioorg Med Chem Lett. 2011 Sep 15;21(18):5625-9. doi: 10.1016/j.bmcl.2011.06.135. Epub 2011 Jul 18.

Structure selectivity relationship studies of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan derivatives toward the development of the mu opioid receptor antagonists.

Author information

1
Department of Medicinal Chemistry, Virginia Commonwealth University, Biotech I, 800 E. Leigh Street, Richmond, VA 23298, United States.

Abstract

Mu opioid receptor antagonists have been applied to target a variety of diseases clinically. The current study is designed to explore the structure selectivity relationship (SSR) of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-pyridyl)carboxamido]morphinan (NAP), a lead compound identified as a selective mu opioid receptor antagonist based on the previous study. Among a series of NAP derivatives synthesized, compounds 6 (NMP) and 9 (NGP) maintained comparable binding affinity, selectivity and efficacy to the lead compound. Particularly, the mu opioid receptor selectivity over kappa opioid receptor of NGP was considerably enhanced compared to that of NAP. Overall, the preliminary SSR supported our original hypothesis that an alternate 'address' domain may exist in the mu opioid receptor, which favors the ligands carrying a hydrogen bond acceptor and an aromatic system to selectively recognize the mu opioid receptor.

PMID:
21788135
PMCID:
PMC3171173
DOI:
10.1016/j.bmcl.2011.06.135
[Indexed for MEDLINE]
Free PMC Article

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