In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an...

A combination of buprenorphine (BUP) and samidorphan (SAM) at a 1:1 (mg/mg) fixed-ratio dose is being investigated as an adjunctive treatment of major depressive disorder (BUP/SAM, ALKS 5461). Both [³H]BUP and [³H]SAM bound to the μ-, κ-, and δ-opioid receptors (MOR, KOR, and DOR, respectively) with K_d values of 3 nM or less. [³H]BUP dissociated from the MOR more slowly than [³H]SAM did. In the [³⁵S]GTPγS assay, BUP was a partial agonist at the MOR, KOR, and DOR. SAM was an antagonist at the MOR and a partial agonist at the KOR and DOR. The pharmacology of the combination of SAM and BUP was characterized at ratios like the molar ratios of both compounds at steady state in humans. In all assessments, SAM reduced the efficacy of BUP at the MOR without altering its potency. At the KOR, SAM had no significant effect on the activity of BUP. In bioluminescent resonance energy transfer assays, SAM, naltrexone, and naloxone were partial agonists when the MOR was coupled to the Gα _oB and Gα _z, and were antagonists when coupled to Gα _i At the KOR, SAM was a partial agonist activating Gα _oA and Gα _oB and a full agonist in stimulating Gα _z SAM inhibited BUP's recruitment of β-arrestin to the MOR, suggesting an attenuation of BUP's efficacy in activating G proteins correlated with an inhibition of β-arrestin recruitment. The collective data suggest that SAM attenuates the efficacy of BUP under all conditions tested at the MOR and DOR but had little effect on BUP activity at the KOR.