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.
(https://doi.org/10.1111/adb.13429)
α4β2 nAChRs for Nicotine Addiction and Substance Use Disorders
Tobacco addiction remains a leading cause of disease and death worldwide, and an increasing number of never- smokers are being exposed to nicotine via e-cigarettes. However, the role of specific nicotinic acetylcholine receptors (nAChR) in nicotine’s behavioral effects remains poorly understood because of the availability of very few subtype-selective probes, which limit drug development potential. Thus, this proposal aims to develop novel probes to better understand the function of the different α4β2 subtypes, which have been proposed to underlie behaviors characteristic of nicotine dependence. The α4β2 nAChR subtypes exhibit two distinct isoforms: α42β23, which has a high affinity for acetylcholine and nicotine, and α43β22 nAChR, which has a lower affinity for acetylcholine and nicotine. Our recent findings have suggested that probes selectively targeting the high sensitivity α42β23 nAChRs may provide a novel, previously undefined understanding of nicotine’s behavioral and pharmacological actions.
(https://doi.org/10.1016/j.neuropharm.2021.108568)