Comparison of pharmacological activities of buprenorphine and norbuprenorphine: Norbuprenorphine is a potent opioid agonist

Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the mai ntenance treatment of opiate-dependent individuals. Although BUP has been s tudied extensively, relatively little is known about norbuprenorphine (norB UP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effec ts on [S-35] guanosine-5'-O-(gamma -thio) triphosphate ([S-35] GTP gammaS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid w rithing test. Chinese hamster ovary cells stably transfected with each rece ptor were used for receptor binding and [S-35] GTP gammaS binding. NorBUP e xhibited high affinities for mu-, delta-, and kappa -opioid receptors with K-i values in the nanomolar or subnanomolar range, comparable to those of B UP. NorBUP and BUP had low affinities for the ORL1 receptor with K-i values in the micromolar range. In the [S-35] GTP gammaS binding assay, norBUP di splayed characteristics distinct from BUP. At the delta -receptor, norBUP w as a potent full agonist, yet BUP had no agonist activity and antagonized a ctions of norBUP and DPDPE. At mu- and kappa -receptors, both norBUP and BU P were potent partial agonists, with norBUP having moderate efficacy and BU P having low efficacy. At the ORL1 receptor, norBUP was a full agonist with low potency, while BUP was a potent partial agonist. In the writhing test, BUP and norBUP both suppressed writhing in an efficacious and dose-depende nt manner, giving A(50) values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and n orBUP, each of which may influence the unique pharmacological profile of BU P.