Wednesday, April 23, 2025
4/23/2025
Selective Probes for Alpha9* Nicotinic Acetylcholine Receptors - Project Summary: Chronic inflammatory and neuropathic pain represents a substantial public health challenge, affecting an estimated 20.9% of U.S. adults, with conventional treatments often limited by efficacy, tolerance, and addiction risks. Recognizing the urgent need for innovative therapeutic strategies, this proposal focuses on the exploration of nicotinic acetylcholine receptors containing the α9 subunit (α9*-nAChR) as novel targets for pain management. Recent advances have highlighted the potential of α9*-nAChR selective modulation to offer significant relief in neuropathic pain conditions through immune cell function regulation, presenting a promising avenue for drug development. Our proposed research aims to address the critical gap in effective pain management by developing and optimizing novel small-molecule probes targeting α9*-nAChRs. These probes are anticipated to demonstrate superior anti-inflammatory and analgesic properties, devoid of the central nervous system side effects associated with opioids. The project is structured around four specific aims, designed to advance our understanding and therapeutic exploitation of α9*-nAChR systematically. Aim 1: We will develop a series of small-molecule agonists and antagonists, utilizing structure-activity relationship (SAR) studies to enhance drug- like attributes, including efficacy, potency, selectivity, solubility, and stability. Computational analyses will guide the optimization process. Aim 2: Novel compounds will undergo rigorous testing to confirm their selectivity and functional activity at α9*-nAChR, employing two-electrode voltage clamp recordings and a comprehensive screening against other human and mouse nAChR subtypes to ensure specificity and minimize side-effect liabilities. Leads that exhibit high potency and selectivity for α9*-nAChR vs. other human and mouse nAChR subtypes will be tested for their inhibitory effect on ATP-mediated release of IL-1β by human mononuclear phagocytes. After passing a Psychoactive Drug Screening Program (PDSP), compounds exhibiting potent anti- inflammatory activities will be profiled pharmacologically (ADME/PK studies). Aim 3: Selected compounds will be evaluated for their absorption, distribution, metabolism, excretion, and pharmacokinetic properties to identify candidates with optimal drug-like characteristics for in vivo efficacy testing. Aim 4: The most promising α9*- nAChR probes will be tested in mouse models of chronic inflammatory and chemotherapy-induced neuropathic pain, aiming to establish their therapeutic potential, side-effect profile, and the sustainability of their analgesic effects upon repeated administration. This interdisciplinary and collaborative project leverages cutting-edge pharmacological, computational, and in vivo methodologies to unveil the therapeutic potential of α9*-nAChR modulation in chronic inflammatory and neuropathic pain treatment. By elucidating the roles of α9*-nAChR in pain pathways and developing novel agonists and antagonists, our research promises to pave the way for the creation of non-addictive, effective pain relief options, thereby addressing a critical unmet medical need and making a significant contribution to pain management and neuropharmacology.
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