Persistent URL

http://hdl.handle.net/10950/5156

Document Type

Poster

Publication Date

3-2026

Abstract

Nicotinic acetylcholine receptors (nAChRs) contribute to the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD), where degeneration of dopaminergic and cholinergic neurons disrupts neurotransmission. The (α4)₃(β2)₂ nAChR subtype is expressed on affected neuronal populations and represents a promising therapeutic target. Positive allosteric modulators (PAMs) may enhance receptor function while preserving endogenous signaling. We evaluated chemical derivatives of CMPI [3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoxazol] as selective PAMs of (α4)₃(β2)₂ nAChRs. Two-electrode voltage-clamp recordings were performed in Xenopus laevis oocytes expressing defined receptor stoichiometries to assess potentiation and generate dose–response curves. Cytotoxicity was assessed in HEK cells using the MTT assay. Substitutions at the pyrazole ring (e.g., thiazole in A12a; imidazole in A12c and A12e) were tolerated within the α4–α4 binding pocket and maintained selectivity for (α4)₃(β2)₂ receptors (EC₅₀ < 1 µM) over (α4)₂(β2)₃ receptors. In contrast, piperidine-to-piperazine modifications reduced or abolished PAM activity. No cytotoxicity was observed at concentrations that potentiated receptor function. Additionally, A12c showed no effect on cell viability up to 100 µM. Computational docking and site-directed mutagenesis supported the extracellular α4–α4 interface as a likely binding site. These findings support further in vitro optimization of CMPI-derived PAMs targeting the (α4)₃(β2)₂ nAChR as a strategy for neurodegenerative disease therapeutics.

Journal/Conference Details

Presented at the UT Tyler School of Medicine Research Day.

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