In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment of Major Depressive Disorder.

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Bidlack JM, Knapp BI, Deaver DR, Plotnikava M, Arnelle D, Wonsey AM, Fern Toh M, Pin SS, Namchuk MN

In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment of Major Depressive Disorder.

J Pharmacol Exp Ther. 2018 Nov;367(2):267-281. doi: 10.1124/jpet.118.249839. Epub 2018 Aug 14.

PubMed ID
30108159 [ View in PubMed
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Abstract

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 [(3)H]BUP and [(3)H]SAM bound to the mu-, kappa-, and delta-opioid receptors (MOR, KOR, and DOR, respectively) with Kd values of 3 nM or less. [(3)H]BUP dissociated from the MOR more slowly than [(3)H]SAM did. In the [(35)S]GTPgammaS 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 Galpha oB and Galpha z, and were antagonists when coupled to Galpha i At the KOR, SAM was a partial agonist activating Galpha oA and Galpha oB and a full agonist in stimulating Galpha z SAM inhibited BUP's recruitment of beta-arrestin to the MOR, suggesting an attenuation of BUP's efficacy in activating G proteins correlated with an inhibition of beta-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.

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