Manipulating Pharmacodynamic Efficacy with Agonist + Antagonist Mixtures: In Vitro and In Vivo Studies with Opioids and Cannabinoids.

Autor: Selley DE; 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.)., Banks ML; 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.)., Diester CM; 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.)., Jali AM; 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.)., Legakis LP; 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.)., Santos EJ; 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.)., Negus SS; 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.) sidney.negus@vcuhealth.org.
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2021 Mar; Vol. 376 (3), pp. 374-384. Date of Electronic Publication: 2020 Dec 22.
DOI: 10.1124/jpet.120.000349
Abstrakt: 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 μ -opioid receptors (MOR) and cannabinoid type 1 receptors (CB 1 R). Mixtures of 1) the MOR agonist fentanyl and antagonist naltrexone and 2) the CB 1 R agonist CP55,940 and antagonist/inverse agonist rimonabant were evaluated in an in vitro assay of ligand-stimulated guanosine 5'- O -(3-[ 35 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.
Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article.
(Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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