Synthesis and in vitro evaluation of salvinorin A analogues: effect of configuration at C(2) and substitution at C(18).
kappa-opioid receptor ligands have raised interest for their apparent effects on mood. The potent and selective kappa-agonist salvinorin A has short-lasting (15min) depressive-like effects in rats in behavioral models used to study mood disorders. Two series of salvinorin derivatives modified at C(2) and C(18), respectively, were synthesized and their kappa-opioid receptor affinities, potencies, and efficacies were evaluated using in vitro receptor binding and biochemical functional assays. Modification at C(2) yielded potent kappa-agonists that are predicted to have improved metabolic stability (14a, 15a) or increased water solubility (10b). Our preliminary SAR study at C(18) suggested that this part of the molecule interacts with a tight lipophilic pocket of the kappa-receptor.
Béguin
Cécile
C
Molecular Pharmacology Laboratory, McLean Hospital, Belmont, MA 02478, USA. cbeguin@mclean.harvard.edu
Richards
Michele R
MR
Li
Jian-Guo
JG
Wang
Yulin
Y
Xu
Wei
W
Liu-Chen
Lee-Yuan
LY
Carlezon
William A
WA
Cohen
Bruce M
BM
D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D002244:Carbon / Q000737:chemistry*; D006224:Cricetinae; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D045785:Diterpenes, Clerodane; D004952:Esters / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000588:Amines; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D004952:Esters; D017473:Receptors, Opioid, kappa; D002244:Carbon; C090499:salvinorin A