The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Nov 2018
In Vitro Pharmacological Characterization of Buprenorphine, Samidorphan, and Combinations Being Developed as an Adjunctive Treatment of Major Depressive Disorder.
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 Kd 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. ⋯ 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 GαoB and Gαz, and were antagonists when coupled to Gαi At the KOR, SAM was a partial agonist activating GαoA and GαoB and a full agonist in stimulating Gαz 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.