Synthetic studies of neoclerodane diterpenes from Salvia divinorum: semisynthesis of salvinicins A and B and other chemical transformations of salvinorin A.
Salvinorin A (1) is a hallucinogenic neoclerodane diterpene isolated from the widely available psychoactive plant Salvia divinorum and is the first example of a non-nitrogenous opioid receptor ligand. At present, there is little information available as to why this compound is selective for kappa opioid receptors. One approach to better understanding the mode of binding of 1 at kappa receptors is to systematically alter the structure of 1 and examine the effects on opioid receptor affinity and activity. Currently, there is a paucity of methods described for the preparation of analogues derived from 1. Here, we report the investigation of several chemical transformations of 1 isolated from S. divinorum. In particular, this work provides a semisynthesis of salvinicins A (2) and B (3) and has identified 10a as the first neoclerodane diterpene with delta opioid antagonist activity.
Harding
Wayne W
WW
Division of Medicinal & Natural Products Chemistry, College of Pharmacy, The University of Iowa, Iowa City, Iowa 52242, USA.
Schmidt
Matthew
M
Tidgewell
Kevin
K
Kannan
Pavitra
P
Holden
Kenneth G
KG
Gilmour
Brian
B
Navarro
Hernan
H
Rothman
Richard B
RB
Prisinzano
Thomas E
TE
D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D010946:Plants, Medicinal / Q000737:chemistry*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors; D027544:Salvia / Q000737:chemistry*; D013237:Stereoisomerism
D004224:Diterpenes; D045785:Diterpenes, Clerodane; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C508456:salvinorin B; C090499:salvinorin A