Characterization of structurally novel G protein biased CB 1 agonists: Implications for drug development.

Autor: Ford BM; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: bmford@uams.edu., Franks LN; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: lnranks@uams.edu., Tai S; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: sytai@med.umich.edu., Fantegrossi WE; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: wefantegrossi@uams.edu., Stahl EL; Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: estahl@scripps.edu., Berquist MD; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: mdberquistii@uams.edu., Cabanlong CV; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: cvcabanlong@uams.edu., Wilson CD; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: cdwilson2@uams.edu., Penthala NR; Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: nrpenthala@uams.edu., Crooks PA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu., Prather PL; Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA. Electronic address: pacrooks@uams.edu.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2017 Nov; Vol. 125 (Pt B), pp. 161-177. Date of Electronic Publication: 2017 Aug 23.
DOI: 10.1016/j.phrs.2017.08.008
Abstrakt: The human cannabinoid subtype 1 receptor (hCB 1 R) is highly expressed in the CNS and serves as a therapeutic target for endogenous ligands as well as plant-derived and synthetic cannabinoids. Unfortunately, acute use of hCB 1 R agonists produces unwanted psychotropic effects and chronic administration results in development of tolerance and dependence, limiting the potential clinical use of these ligands. Studies in β-arrestin knockout mice suggest that interaction of certain GPCRs, including μ-, δ-, κ-opioid and hCB 1 Rs, with β-arrestins might be responsible for several adverse effects produced by agonists acting at these receptors. Indeed, agonists that bias opioid receptor activation toward G-protein, relative to β-arrestin signaling, produce less severe adverse effects. These observations indicate that therapeutic utility of agonists acting at hCB 1 Rs might be improved by development of G-protein biased hCB 1 R agonists. Our laboratory recently reported a novel class of indole quinulidinone (IQD) compounds that bind cannabinoid receptors with relatively high affinity and act with varying efficacy. The purpose of this study was to determine whether agonists in this novel cannabinoid class exhibit ligand bias at hCB 1 receptors. Our studies found that a novel IQD-derived hCB 1 receptor agonist PNR-4-20 elicits robust G protein-dependent signaling, with transduction ratios similar to the non-biased hCB 1 R agonist CP-55,940. In marked contrast to CP-55,940, PNR-4-20 produces little to no β-arrestin 2 recruitment. Quantitative calculation of bias factors indicates that PNR-4-20 exhibits from 5.4-fold to 29.5-fold bias for G protein, relative to β-arrestin 2 signaling (when compared to G protein activation or inhibition of forskolin-stimulated cAMP accumulation, respectively). Importantly, as expected due to reduced β-arrestin 2 recruitment, chronic exposure of cells to PNR-4-20 results in significantly less desensitization and down-regulation of hCB 1 Rs compared to similar treatment with CP-55,940. PNR-4-20 (i.p.) is active in the cannabinoid tetrad in mice and chronic treatment results in development of less persistent tolerance and no significant withdrawal signs when compared to animals repeatedly exposed to the non-biased full agoinst JWH-018 or Δ 9 -THC. Finally, studies of a structurally similar analog PNR- 4-02 show that it is also a G protein biased hCB 1 R agonist. It is predicted that cannabinoid agonists that bias hCB 1 R activation toward G protein, relative to β-arrestin 2 signaling, will produce fewer and less severe adverse effects both acutely and chronically.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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