Synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A.
Lu Yang, Wei Xu, Feng Chen, Lee-Yuan Liu-Chen, Zhongze Ma, David Y W Lee
Bioorganic & medicinal chemistry letters March 1, 2009 DOI: 10.1016/j.bmcl.2009.01.078 via PubMed
Summary
AI-generated from the abstractSalvinorin A, the main active ingredient of Salvia divinorum, is a potent and selective kappa-opioid receptor agonist. A series of C-12 triazole analogs and an oxadiazole analog were synthesized and tested for binding affinity at kappa, mu, and delta opioid receptors. Surprisingly, all triazole analogs showed negligible binding affinity at opioid receptors, and the oxadiazole analog, previously reported as a mu and kappa opioid receptor antagonist, exhibited very low affinities and no antagonism in the binding assays. These results suggest that electronic factors affecting either the electron density of a hydrogen bond acceptor at C-12 or hydrophobic interactions between the C-12 moiety and the kappa-opioid receptor are critical for C-12 analog affinity.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Key finding | C-12 triazole analogs of salvinorin A show negligible binding affinity at opioid receptors, and the oxadiazole analog exhibits very low affinities and no antagonism, indicating that electronic and hydrophobic factors at C-12 are critical for kappa-opioid receptor affinity. |
Abstract
Salvinorin A (1), the main active ingredient of Salvia divinorum, is a potent and selective kappa-opioid receptor (KOPR) agonist. A series of C-12 triazole analogs and the oxadiazole (4) analog of 1 are synthesized and screened for binding affinity at kappa, mu (MOPR), or delta (DOPR). Surprisingly, all triazole analogs have shown negligible binding affinity at opioid receptors and the oxadiazole 4, a reported MOPR and KOPR antagonist, exhibits very low affinities to opioid receptors and no antagonism in our binding assays. These results suggest that electronic factors that may affect either the electron density of hydrogen bond acceptor at C-12 or hydrophobic interactions between C-12 moiety and KOPR are critical to C-12 analog's affinity for KOPR.