Pharmacological selection of cannabinoid receptor effectors: Signalling, allosteric modulation and bias.

Autor: Manning JJ; Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand., Green HM; Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand., Glass M; Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand., Finlay DB; Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand, PO Box 56, Dunedin, 9054, New Zealand. Electronic address: david.finlay@otago.ac.nz.
Jazyk: angličtina
Zdroj: Neuropharmacology [Neuropharmacology] 2021 Aug 01; Vol. 193, pp. 108611. Date of Electronic Publication: 2021 May 15.
DOI: 10.1016/j.neuropharm.2021.108611
Abstrakt: The type-1 cannabinoid receptor (CB 1 ) is a promising drug target for a wide range of diseases. However, many existing and novel candidate ligands for CB 1 have shown only limited therapeutic potential. Indeed, no ligands are currently approved for the clinic except formulations of the phytocannabinoids Δ 9 -THC and CBD and a small number of analogues. A key limitation of many promising CB 1 ligands are their on-target adverse effects, notably including psychoactivity (agonists) and depression/suicidal ideation (inverse agonists). Recent drug development attempts have therefore focussed on altering CB 1 signalling profiles in two ways. Firstly, with compounds that enhance or reduce the signalling of endogenous (endo-) cannabinoids, namely allosteric modulators. Secondly, with compounds that probe the capability of selectively targeting specific cellular signalling pathways that may mediate therapeutic effects using biased ligands. This review will summarise the current paradigm of CB 1 signalling in terms of the intracellular transduction pathways acted on by the receptor. The development of compounds that selectively activate CB 1 signalling pathways, whether allosterically or via orthosteric agonist bias, will also be addressed.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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