Nicotinic Acetylcholine Receptor – α4β2, α7, α9

Nicotinic acetylcholine receptors (nAChR’s) are ion channels present in the central and peripheral nervous system, muscle, and many other tissues. Activated by endogenous acetylcholine, nAChR’s are implicated in many conditions like neuropathic pain (α9, α7) nicotine addiction (α4β2), cognitive dysfunction (α4β2), attention deficit hyperactivity disorder (ADHD; α4β2), depression (α4β2), Parkinson’s disease (α4β2), alcohol addiction (α4β2), etc.
Our research is focused on the development of novel selective ligands that selectively target one or more nAChRs to deliver better therapeutics

α4β2 nAChRs for Nicotine Addiction and Cognition
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)

α9 nAChRs in 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 in Cognition, Inflamation and 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)