Positive Allosteric Modulation of CB1 and CB2 Cannabinoid Receptors Enhances the Neuroprotective Activity of a Dual CB1R/CB2R Orthosteric Agonist

Abstract

Preclinical studies highlighted that compounds targeting cannabinoid receptors could be useful for developing novel therapies against neurodegenerative disorders. However, the chronic use of orthosteric agonists alone has several disadvantages, limiting their usefulness as clinically relevant drugs. Positive allosteric modulators might represent a promising approach to achieve the potential therapeutic benefits of orthosteric agonists of cannabinoid receptors through increasing their activity and limiting their adverse effects. The aim of the present study was to show the effects of positive allosteric ligands of cannabinoid receptors on the activity of a potent dual orthosteric agonist for neuroinflammation and excitotoxic damage by excessive glutamate release. The results indicate that the combination of an orthosteric agonist with positive allosteric modulators could represent a promising therapeutic approach to the treatment of neurodegenerative disorders.

Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB2 Receptor Derived from the Natural Product Cannabidiol

“…This limitation can be avoided by designing ligands that act on CB 2 R, instead of CB 1 R, due to their lack of adverse psychotropic effects 44 and designing PAMs that increase the response of the orthosteric endogenous agonist to limit adverse effects. 19 Accordingly, we have designed and synthesized in this article PAMs of CB 2 R using the natural product CBD as a scaffold that might be useful for the treatment of pain without producing tolerance or dependence. 45,46 ■ EXPERIMENTAL SECTION Synthetic Procedures and Compound Characterization.…”

“…This knowledge has permitted to perform structure-guided design of NAMs and positive allosteric modulators (PAMs) of CB 2 R. The designed compounds are relevant because the combination of orthosteric agonists with PAMs could represent a therapeutic approach for neurodegenerative disorders and neuropathic pain. 19 Until now, the only reported allosteric modulators of CB 2 R, in addition to CBD, 15 are PAMs: the endogenous 12-residue peptide pepcan-12 20 and a synthetic small molecule. 21 ■ RESULTS AND DISCUSSION CBD Is Both a Partial Agonist and a Negative Allosteric Modulator.…”

Reactive Astrocytosis in a Mouse Model of Chronic Polyamine Catabolism Activation

“…Gliosomes are a purified preparation of astrocyte processes containing vesicles loaded with gliotransmitter, competent for gliotransmitter secretion [ 9 , 19 ]. Synaptosomes are a purified preparation of nerve terminals, negligibly contaminated by astrocytic, microglial or oligodendroglial particles, competent for the release of neurotransmitters in response to different stimulations [ 20 , 24 , 25 ]. Gliosomes and synaptosomes were washed by centrifugation, and the pellets were resuspended in standard physiological medium buffered with HEPES or in loading buffer for the WB analysis.…”

Endocannabinoid Modulation in Neurodegenerative Diseases: In Pursuit of Certainty

“…In an experimental malonate-rat model of HD, an increase in CB2R could be observed in reactive microglial cells and in activated astrocytes within the striatum [141]. Unlike CB1R orthosteric agonists, which induce psychotropic effects, mood alterations, cognitive and motor impairments and acute psychosis, CB2R ligands appear to be promising drugs for treating neuro-inflammatory diseases [142] because they do not induce the undesirable psychotropic effects. Thus, CB2R activation is associated with a neuroprotective effect in HD models through controlling the damaging activity of the microglia [140].…”