The Binding Mode to Orthosteric Sites And/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB Receptors

Overview

Journal Front Pharmacol

Date 2022 Mar 7

PMID 35250601

Authors

Rafael Franco

Paula Morales

Gemma Navarro

Nadine Jagerovic

Irene Reyes-Resina

Affiliations

Soon will be listed here.

Abstract

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB receptor (CBR) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CBR conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CBR ligands in order to fine-tune signaling effects and therapeutic propositions.

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