Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (D.E.S., M.L.B., C.M.D., A.M.J., L.P.L., E.J.S., S.S.N.) and Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, Saudi Arabia (A.M.J.).
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia (D.E.S., M.L.B., C.M.D., A.M.J., L.P.L., E.J.S., S.S.N.) and Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan, Saudi Arabia (A.M.J.)
J Pharmacol Exp Ther. 2021 Mar;376(3):374-384. doi: 10.1124/jpet.120.000349. Epub 2020 Dec 22.
Pharmacodynamic efficacy of drugs to activate their receptors is a key determinant of drug effects, and intermediate-efficacy agonists are often useful clinically because they retain sufficient efficacy to produce therapeutically desirable effects while minimizing undesirable effects. Molecular mechanisms of efficacy are not well understood, so rational drug design to control efficacy is not yet possible; however, receptor theory predicts that fixed-proportion mixtures of an agonist and antagonist for a given receptor can be adjusted to precisely control net efficacy of the mixture in activating that receptor. Moreover, the agonist proportion required to produce different effects provides a quantitative scale for comparing efficacy requirements across those effects. To test this hypothesis, the present study evaluated effectiveness of fixed-proportion agonist/antagonist mixtures to produce in vitro and in vivo effects mediated by -opioid receptors (MOR) and cannabinoid type 1 receptors (CBR). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CBR agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'--(3-[S]thio)triphosphate binding and an in vivo assay of thermal nociception in mice. For both agonist/antagonist pairs in both assays, increasing agonist proportions produced graded increases in maximal mixture effects, and lower agonist proportions were sufficient to produce in vivo than in vitro effects. These findings support the utility of agonist-antagonist mixtures as a strategy to control net efficacy of receptor activation and to quantify and compare efficacy requirements across a range of in vitro and in vivo endpoints. SIGNIFICANCE STATEMENT: Manipulation of agonist proportion in agonist/antagonist mixtures governs net mixture efficacy at the target receptor. Parameters of agonist/antagonist mixture effects can provide a quantitative metric for comparison of efficacy requirements across a wide range of conditions.
药物激活其受体的药效学效力是药物作用的关键决定因素，中等效力激动剂在临床上通常很有用，因为它们保留了足够的效力以产生治疗上所需的效果，同时最小化不良效果。药效学的分子机制尚未得到很好的理解，因此还不可能进行合理的药物设计来控制药效；然而，受体理论预测，对于给定的受体，一种激动剂和一种拮抗剂的固定比例混合物可以进行调整，以精确控制该混合物激活该受体的净效力。此外，产生不同效果所需的激动剂比例为比较这些效果的效力要求提供了一个定量尺度。为了检验这一假设，本研究评估了固定比例激动剂/拮抗剂混合物在体外和体内产生 - 阿片受体（MOR）和大麻素 1 型受体（CBR）介导的效果的有效性。评估了 1）MOR 激动剂芬太尼和拮抗剂纳曲酮的混合物和 2）CBR 激动剂 CP55,940 和拮抗剂/反向激动剂利莫那班的混合物在体外配体刺激鸟苷 5'--（3-[S]硫）三磷酸结合测定和体内小鼠热痛觉测定中的作用。对于这两种激动剂/拮抗剂对在这两种测定中，随着激动剂比例的增加，混合物的最大效果呈梯度增加，并且在体内产生效果所需的激动剂比例低于体外。这些发现支持使用激动剂-拮抗剂混合物作为控制受体激活净效力的策略，并对体外和体内一系列终点的效力要求进行量化和比较。
在激动剂/拮抗剂混合物中操纵激动剂比例控制靶受体的净混合物效力。激动剂/拮抗剂混合物效果的参数可以提供一种定量指标，用于比较广泛条件下的效力要求。
