Cannabinoid Receptors – CB1, CB2

Cannabinoid Allosteric Modulators for Neuropathic pain 
Safe and effective treatment of neuropathic pain remains a challenging medical problem. First- and second-line treatments show modest, variable efficacies in treating neuropathic pain and carry serious liabilities. Orthosteric CB1R agonists like delta-9-tetrahydrocannabinol show (pre)clinical efficacy in suppressing neuropathic nociception but also produce unwanted side-effects (e.g., tolerance, physical dependence, psychoactivity). CB2R agonists (GW842166X, S-777469, and JBT-101) have not shown efficacy in clinical trials in other indications and have not been tested for efficacy in people in therapeutic indications supported by the preclinical literature.

CB1 Positive Allosteric Modulators 
A new class of ligands has been identified for CB1 cannabinoid receptors -PAMs. These compounds enhance CB1 receptor activation at a secondary site by increasing the CB1 affinity of direct agonists and /or the ability of such agonists to induce CB1 receptor signaling. Because they are expected to affect the functioning of CB1 receptors that are already being activated endogenously, PAMs should avoid some of the risks of global ocular CB1 receptor activation, including off-target activation and desensitization that come with the use of an orthosteric agonist. We demonstrated that GAT211 suppressed allodynia induced by complete Freund’s adjuvant and the chemotherapeutic agent paclitaxel in wild-type but not CB1 knockout mice. GAT211 did not impede paclitaxel-induced tumor cell line toxicity. GAT211 did not produce cardinal signs of direct CB1-receptor activation in the presence or absence of pathological pain. GAT211 produced synergistic antiallodynic effects with fatty acid amide hydrolase and monoacylglycerol lipase inhibitors in paclitaxel-treated mice. Therapeutic efficacy was preserved over 19 days of chronic dosing with GAT211, but it was not preserved with the monoacylglycerol lipase inhibitor JZL184. The CB1 antagonist rimonabant precipitated withdrawal in mice treated chronically with WIN55,212-2 but not in mice treated with GAT211. GAT211 did not induce conditioned place preference or aversion. This work demonstrated that Positive allosteric modulation of CB1-receptor signaling shows promise as a safe and effective analgesic strategy that lacks tolerance, dependence, and abuse liability.

CB1/CB2 Dualsteric Modulators
Very recently, we have successfully identified novel “dualsteric modulators” having a unique pharmacological phenotype characterized by activity as both a non-psychoactive cannabinoid CB1R allosteric agonist-positive allosteric modulator (ago-PAM) and a CB2R agonist. Our central hypothesis is that such dualsteric ligands leverage the therapeutic advantages of allosteric GPCR regulation of both cannabinoid receptors and provide effective broad-spectrum analgesia without abuse liability and other CB1R-mediated side effects.

CB1 Negative Allosteric Modulators and Treatment for Substance Use Disorders:
The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators. We hypothesized that negative allosteric modulation of CB1R signaling would reduce the reinforcing properties of morphine and decrease behaviors associated with opioid misuse. By employing intravenous self-administration in mice, we studied the effects of GAT358, a functionally-biased CB1R negative allosteric modulator (NAM), on morphine intake, relapse-like behavior and motivation to work for morphine infusions.
GAT358, a CB1 NAM, failed to elicit cardinal signs of direct CB1 activation or inactivation when administered by itself. GAT358 decreased catalepsy and hypothermia but not antinociception produced by the orthosteric CB1 agonist CP55,940, suggesting that a CB1 NAM blocked cardinal signs of CB1 activation. Next, GAT358 was evaluated using in vivo assays of opioid-induced dopamine release and reward in male rodents. In the nucleus accumbens shell, a key component of the mesocorticolimbic reward pathway, morphine increased electrically-evoked dopamine efflux and this effect was blocked by a dose of GAT358 that lacked intrinsic effects on evoked dopamine efflux. Moreover, GAT358 blocked morphine-induced reward in a conditioned place preference (CPP) assay without producing reward or aversion alone. GAT358-induced blockade of morphine CPP was also occluded by GAT229, a CB1 positive allosteric modulator (CB1 PAM), and absent in CB1-knockout mice. Finally, GAT358 also reduced oral oxycodone (but not water) consumption in a two-bottle choice paradigm.  Our results also demonstrated that GAT358 reduced the reinforcing properties of morphine and could represent a viable therapeutic route to safely decrease misuse of opioids.