Therapeutic Targets
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.
(https://doi.org/10.3389/fphar.2022.919605)
α9 nAChRs for Neuropathic pain
There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. In our studies, we introduce novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, we have identified novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.
(J. Med. Chem. 2024. https://doi.org/10.1021/acs.jmedchem.3c02429)
α7 nAChRs for Neuropathic pain
The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Structure-guided functional and computational tests suggest that differences in modulator activity arise from the stable rotation of a channel gating residue out of the pore. Using time-resolved cryoelectron microscopy (cryo-EM), we have revealed an asymmetric state transitions for this homomeric channel and also find that a modulator with allosteric agonist activity exploits a distinct channel-gating mechanism. These results define mechanisms of α7 allosteric modulation and activation with implications across the pentameric receptor superfamily.
(Cell, Vol. 187, Issue 5, 2024. https://doi.org/10.1016/j.cell.2024.01.032)