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, 56 (8), 3207-16

Orvinols With Mixed Kappa/Mu Opioid Receptor Agonist Activity

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Orvinols With Mixed Kappa/Mu Opioid Receptor Agonist Activity

Benjamin M Greedy et al. J Med Chem.

Abstract

Dual-acting kappa opioid receptor (KOR) agonist and mu opioid receptor (MOR) partial agonist ligands have been put forward as potential treatment agents for cocaine and other psychostimulant abuse. Members of the orvinol series of ligands are known for their high binding affinity to both KOR and MOR, but efficacy at the individual receptors has not been thoroughly evaluated. In this study, it is shown that a predictive model for efficacy at KOR can be derived, with efficacy being controlled by the length of the group attached to C20 and by the introduction of branching into the side chain. In vivo evaluation of two ligands with the desired in vitro profile confirms both display KOR, and to a lesser extent MOR, activity in an analgesic assay suggesting that, in this series, in vitro measures of efficacy using the [(35)S]GTPγS assay are predictive of the in vivo profile.

Figures

Scheme 1
Scheme 1
Scheme 2
Scheme 2
Figure 1
Figure 1
Two views of the areas, predicted by COMFA analysis, where interaction with a lipophilic group would be beneficial for KOR activation (shown in green) and where interaction with a lipophilic group would be detrimental to efficacy (shown in yellow).
Figure 2
Figure 2
KOR with the protein in green, the crystal structure ligand (JDTic) in cyan, and the docked buprenorphine (1n) in pink. The hydrogen bond between the docked ligand and Asp138 is shown as the black dashed line.
Figure 3
Figure 3
MOR with the protein in green, the crystal structure ligand (β-FNA) in cyan, and the docked buprenorphine (1n) in pink. The hydrogen bond between the docked ligand and Asp147 is shown as the black dashed line.

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