Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2).
Salvinorin A is the only known non-nitrogenous and specific kappa-opioid agonist. A series of salvinorin A derivatives were prepared and tested for in vitro activity at the kappa-opioid receptor. Unsubstituted carbamate 9 was a potent kappa-agonist (EC(50) = 6.2 nM) and should be more stable than salvinorin A toward metabolic transformations. Compound 10, containing an N-methyl carbamate at C(2), showed partial agonist activity with 81% efficacy when compared with the full agonist U50,488H. No antagonist ligands were observed.
Béguin
Cécile
C
Molecular Pharmacology Laboratory, McLean Hospital, Belmont, MA 02478, USA.
Richards
Michele R
MR
Wang
Yulin
Y
Chen
Yong
Y
Liu-Chen
Lee-Yuan
LY
Ma
Zhongze
Z
Lee
David Y W
DY
Carlezon
William A
WA
Cohen
Bruce M
BM
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004353:Drug Evaluation, Preclinical
D004224:Diterpenes; D045785:Diterpenes, Clerodane; C090499:salvinorin A