Modification of the furan ring of salvinorin A: identification of a selective partial agonist at the kappa opioid receptor.
In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Introducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadiazoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR antagonism or any affinity for mu or delta opioid receptors.
Béguin
Cécile
C
Mailman Research Center, McLean Hospital, Belmont, MA 02478, USA. cbeguin@mclean.harvard.edu
Duncan
Katharine K
KK
Munro
Thomas A
TA
Ho
Douglas M
DM
Xu
Wei
W
Liu-Chen
Lee-Yuan
LY
Carlezon
William A
WA
Cohen
Bruce M
BM
D045785:Diterpenes, Clerodane / Q000138:chemical synthesis / Q000737:chemistry*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013329:Structure-Activity Relationship
D045785:Diterpenes, Clerodane; D005663:Furans; D017473:Receptors, Opioid, kappa; C090499:salvinorin A