Allosteric Modulation: An Alternate Approach Targeting the Cannabinoid CB1 Receptor

Abstract

The cannabinoid CB1 receptor is a G protein-coupled receptor and plays an important role in many biological processes and physiological functions. A variety of CB1 receptor agonists and antagonists, including endocannabinoids, phytocannabinoids and synthetic cannabinoids have been discovered or developed over the past 20 years. In 2005 it was discovered that the CB1 receptor contains allosteric site(s) which can be recognized by small molecules, or allosteric modulators. A number of CB1 receptor allosteric modulators, both positive and negative, have since been reported and importantly, they display pharmacological characteristics that are distinct from those of orthosteric agonists and antagonists. Given the psychoactive effects commonly associated with CB1 receptor agonists and antagonists/inverse agonists, allosteric modulation may offer an alternate approach to attain potential therapeutic benefits while avoiding inherent side effects of orthosteric ligands. This review details the complex pharmacological profiles of these allosteric modulators, their structure-activity relationships, and efforts in elucidating binding modes and mechanisms of actions of reported CB1 allosteric modulators. The ultimate development of CB1 receptor allosteric ligands could potentially lead to improved therapies for CB1-mediated neurological disorders.

Novel Diarylurea Based Allosteric Modulators of the Cannabinoid CB1 Receptor: Evaluation of Importance of 6-Pyrrolidinylpyridinyl Substitution

“…8 Consistent with previous reports, 9, 13, 27 2 dose-dependently decreased the E max value of [ 35 S]GTP-γ-S binding levels stimulated by CP55,940 as expected for CB1 NAMs (Fig. 4A).…”

“…8 Unlike 1, which displays agonist activities in some assays such as ERK phosphorylation, 13, 14 2 showed little or no activity in the absence of an orthosteric agonist in many assays investigated thus far. 8 …”

“…8 These include CB1 receptor NAMs such as PSNCBAM-1 ( 2 ) 9 , fenofibrate ( 3 ), 10 and CB1 receptor PAMs ZCZ011 ( 4 ) 11 and GAT211 ( 5 ) 12 (Fig. 1).…”

Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence

“…Binding of a pure positive allosteric modulator (PAM) to an allosteric site increases the affinity of the endogenous ligand for the orthosteric binding site and/or enhances the efficiency of signaling by the endogenous ligand(21, 22). By amplifying ongoing signaling by endogenous agonists, allosteric modulators may produce a more optimal and circumscribed spectrum of physiological effects compared to indiscriminate activation of cannabinoid receptors.…”

The great divide: Separation between in vitro and in vivo effects of PSNCBAM-based CB 1 receptor allosteric modulators

“…Allosteric modulation allows for the fine-tuning of receptor pharmacology which may facilitate signaling bias towards pathways that are more therapeutically relevant while avoiding those involved in the untoward effects. There are now a handful of molecules which exhibit allosteric properties at the CB 1 receptor (for reviews see Morales et al, 2016; Nguyen et al, 2016). The majority of reported allosteric modulators differentially affect radioligand binding, exhibiting positive binding cooperativity with the CB 1 /CB 2 agonist [ 3 H]CP55,940 and negative binding cooperativity with the selective CB 1 antagonist [ 3 H]SR141716.…”