Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York (J.M.B., B.I.K.) and Alkermes, Inc., Waltham, Massachusetts (D.R.D., M.P., D.A., A.M.W., M.F.T., S.S.P., M.N.N.)
Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, New York (J.M.B., B.I.K.) and Alkermes, Inc., Waltham, Massachusetts (D.R.D., M.P., D.A., A.M.W., M.F.T., S.S.P., M.N.N.).
J Pharmacol Exp Ther. 2018 Nov;367(2):267-281. doi: 10.1124/jpet.118.249839. Epub 2018 Aug 14.
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 [H]BUP and [H]SAM bound to the -, -, and -opioid receptors (MOR, KOR, and DOR, respectively) with K values of 3 nM or less. [H]BUP dissociated from the MOR more slowly than [H]SAM did. In the [S]GTPS 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 G and G , and were antagonists when coupled to G At the KOR, SAM was a partial agonist activating G and G and a full agonist in stimulating G SAM inhibited BUP's recruitment of -arrestin to the MOR, suggesting an attenuation of BUP's efficacy in activating G proteins correlated with an inhibition of -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.
布比卡因（BUP）和萨米多弗（SAM）以 1:1（mg/mg）固定比例剂量联合使用，作为治疗重度抑郁症的辅助治疗（BUP/SAM，ALKS 5461）。[H]BUP 和 [H]SAM 分别以 3 nM 或更低的 K 值与 μ-、κ-和 δ-阿片受体（MOR、KOR 和 DOR）结合。[H]BUP 从 MOR 解离的速度比 [H]SAM 慢。在 [S]GTPS 测定中，BUP 是 MOR、KOR 和 DOR 的部分激动剂。SAM 是 MOR 的拮抗剂，也是 KOR 和 DOR 的部分激动剂。SAM 和 BUP 的组合的药理学特征与在人类中两种化合物在稳定状态下的摩尔比相似。在所有评估中，SAM 降低了 BUP 在 MOR 上的效力，而不改变其效力。在 KOR 上，SAM 对 BUP 的活性没有显著影响。在生物发光共振能量转移测定中，当 MOR 与 G 和 G 偶联时，SAM、纳曲酮和纳洛酮是部分激动剂，而当与 G 偶联时，它们是拮抗剂。在 KOR 上，SAM 是激活 G 和 G 的部分激动剂，也是刺激 G 的完全激动剂。SAM 抑制 BUP 募集 -arrestin 到 MOR，表明 BUP 激活 G 蛋白的效力降低与 -arrestin 募集的抑制相关。综合数据表明，SAM 在 MOR 和 DOR 下的所有测试条件下都降低了 BUP 的效力，但对 KOR 上 BUP 的活性影响不大。
