Synthetic studies of neoclerodane diterpenes from Salvia divinorum: exploration of the 1-position.
Modification of the C-1 ketone of salvinorin A (2a) produces analogues with opioid antagonist properties. Of particular significance is the finding that 1-deoxo-1,10-dehydrosalvinorin A (11a) is a moderately potent antagonist at all three opioid receptor subtypes, and that herkinorin (2b), a mu agonist, is converted to a weak antagonist by removal of the C-1 ketone (3b and 11b). These observations suggest that the ketone of 2b is a key structural feature responsible for mu agonist activity.
Holden
Kenneth G
KG
Holden Laboratories, Carmel, CA 93923, USA.
Tidgewell
Kevin
K
Marquam
Alfred
A
Rothman
Richard B
RB
Navarro
Hernán
H
Prisinzano
Thomas E
TE
D001667:Binding, Competitive / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045785:Diterpenes, Clerodane / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015394:Molecular Structure; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D027544:Salvia / Q000737:chemistry*; D013329:Structure-Activity Relationship
C502982:9-(benzoyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho(2,1-c)pyran-7-carboxylic acid methyl ester; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D005663:Furans; D011753:Pyrones; D017450:Receptors, Opioid, mu; D011994:Recombinant Proteins; C468586:neoclerodane; C090499:salvinorin A