Synthesis and biological evaluation of C-12 triazole and oxadiazole analogs of salvinorin A.
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.
Yang
Lu
L
Bio-Organic and Natural Products Laboratory, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA.
Xu
Wei
W
Chen
Feng
F
Liu-Chen
Lee-Yuan
LY
Ma
Zhongze
Z
Lee
David Y W
DY
D000818:Animals; D016466:CHO Cells; D002244:Carbon / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D045785:Diterpenes, Clerodane / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D045785:Diterpenes, Clerodane; D010069:Oxadiazoles; D014230:Triazoles; D002244:Carbon; C090499:salvinorin A