C7β-Methyl Analogues of the Orvinols: The Discovery of Kappa Opioid Antagonists with Nociceptin/Orphanin FQ Peptide (NOP) Receptor Partial Agonism and Low, or Zero, Efficacy at Mu Opioid Receptors

Abstract

Buprenorphine is a successful analgesic and treatment for opioid abuse, with both activities relying on its partial agonist activity at mu opioid receptors. However, there is substantial interest in its activities at the kappa opioid and nociceptin/orphanin FQ peptide receptors. This has led to an interest in developing compounds with a buprenorphine-like pharmacological profile but with lower efficacy at mu opioid receptors. The present article describes aryl ring analogues of buprenorphine in which the standard C20-methyl group has been moved to the C7β position, resulting in ligands with the desired profile. In particular, moving the methyl group has resulted in far more robust kappa opioid antagonist activity than seen in the standard orvinol series. Of the compounds synthesized, a number, including 15a, have a profile of interest for the development of drug abuse relapse prevention therapies or antidepressants and others (e.g., 8c), as analgesics with a reduced side-effect profile.

Antidepressant‐like effects of BU10119, a novel buprenorphine analogue with mixed κ/μ receptor antagonist properties, in mice

“…We have previously shown that the combined administration of buprenorphine and naltrexone produces antidepressant‐like effects in mice (Almatroudi et al, ). BU10119 is a recently reported novel compound with an in vitro pharmacology that resembles the combination of buprenorphine/naltrexone: high affinity/zero efficacy at κ receptors, high affinity/little efficacy at μ receptors and a weak partial agonist profile at NOP receptors (Cueva et al, ). Here, we report for the first time the in vivo pharmacology of BU10119 in adult male CD1 mice.…”

“…BU10119 was synthesized and supplied at the University of Bath (Cueva et al, ). Buprenorphine hydrochloride and morphine sulphate were purchased from MacFarlan Smith (Edinburgh, UK).…”

“…This would overcome both the abuse liability issue and the dosing issues. BU10119 is one of a novel series of orvinol analogues in which the C20‐methyl group has been moved to the C7‐b position (Cueva et al, ; Figure ). In vitro pharmacology studies have established that BU10119 has high affinity for both κ and μ receptors with little efficacy at either of these receptors indicating an antagonist‐like profile (Cueva et al, ; Table ).…”

“…BU10119 is one of a novel series of orvinol analogues in which the C20‐methyl group has been moved to the C7‐b position (Cueva et al, ; Figure ). In vitro pharmacology studies have established that BU10119 has high affinity for both κ and μ receptors with little efficacy at either of these receptors indicating an antagonist‐like profile (Cueva et al, ; Table ). Here, we report the initial characterization of BU10119 in vivo and behavioural studies that demonstrate the therapeutic antidepressant‐like potential in mice.…”

“…Neither buprenorphine nor BU10119 has any appreciable efficacy at δreceptors. All data taken from Cueva et al ., . *1a and *15a are the identifiers used for these compounds in Cueva et al ., .…”