Ring-constrained orvinols as analogs of buprenorphine: differences in opioid activity related to configuration of C(20) hydroxyl group.
The relative positions of the C(20) substituents in buprenorphine, particularly the hydroxyl group, have been implicated in its actions as a partial mu-agonist and a kappa-antagonist. This hypothesis has been examined by the synthesis and pharmacological characterization of five orvinols in which the C(20) carbon atom of buprenorphine is constrained in a five-membered ring, fixing the hydroxyl group above (beta) or below (alpha) the plane of the ring. All five compounds were nonselective in binding assays with similar, low nanomolar affinities. The compounds acted as delta-agonists in the mouse vas deferens and kappa-agonists in the myenteric plexus-longitudinal muscle of the guinea pig ileum and in Chinese hamster ovary (CHO) cells expressing the human kappa-opioid receptor (CHO-hkor). All were lower efficacy mu-agonists than buprenorphine as measured by the [(35)S]guanosine-5'-O-(3-thio)triphosphate assay in SH-SY5Y cells. The major difference between the isomers was an 11- to 12-fold higher potency of the beta-OH isomer (BU46) compared with the alpha-OH isomer (BU47) at the kappa-receptor in the guinea pig ileum and CHO-hkor cells and a somewhat higher efficacy of BU46 in CHO-hkor cells. BU46 and BU47 were evaluated in vivo. BU46 was a full agonist in the mouse writhing assay and antinociception was prevented by norbinaltorphimine, showing a kappa-mechanism of action. In contrast, BU47 acted as an antagonist of mu-, delta-, and kappa-mediated antinociception in the writhing assay. The results show that the configuration of the hydroxyl group is not important in binding affinity at mu-, delta-, or kappa-receptors but does influence kappa-potency and kappa-efficacy, particularly in vivo.
Traynor
J R
JR
Department of Chemistry, Loughborough University, UK. jtraynor@umich.edu
Guo
L
L
Coop
A
A
Lewis
J W
JW
Woods
J H
JH
D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011957:Receptors, Opioid / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002047:Buprenorphine