Comparison of Pharmacological Activities of Buprenorphine and Norbuprenorphine: Norbuprenorphine Is a Potent Opioid Agonist

TLDR: The binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [(35)S]guanosine-5'-O-(gamma-thio)triphosphate ([(35]S]GTP gamma S) binding mediated by opioid or ORL1 receptors are described and highlighted.

Abstract: Buprenorphine (BUP) is an oripavine analgesic that is beneficial in the maintenance treatment of opiate-dependent individuals. Although BUP has been studied extensively, relatively little is known about norbuprenorphine (norBUP), a major dealkylated metabolite of BUP. We now describe the binding of norBUP to opioid and nociceptin/orphanin FQ (ORL1) receptors, and its effects on [35S]guanosine-5′-O-(γ-thio)triphosphate ([35S]GTPγS) binding mediated by opioid or ORL1 receptors and in the mouse acetic acid writhing test. Chinese hamster ovary cells stably transfected with each receptor were used for receptor binding and [35S]GTPγS binding. NorBUP exhibited high affinities for μ-, δ-, and κ-opioid receptors withKi values in the nanomolar or subnanomolar range, comparable to those of BUP. NorBUP and BUP had low affinities for the ORL1 receptor with Ki values in the micromolar range. In the [35S]GTPγS binding assay, norBUP displayed characteristics distinct from BUP. At the δ-receptor, norBUP was a potent full agonist, yet BUP had no agonist activity and antagonized actions of norBUP and DPDPE. At μ- and κ-receptors, both norBUP and BUP were potent partial agonists, with norBUP having moderate efficacy and BUP 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-dependent manner, giving A50 values of 0.067 and 0.21 mg/kg, s.c., respectively. These results highlight the similarities and differences between BUP and norBUP, each of which may influence the unique pharmacological profile of BUP.