Persistent URL

http://hdl.handle.net/10950/5154

Document Type

Poster

Publication Date

11-2023

Abstract

The (α4)3(β2)2 nicotinic acetylcholine receptor (nAChR) is the major heteromeric nAChR isoform expressed in the cortex and is believed to play a role in memory, cognition, and neuronal survival during aging. As such, selective potentiators of the (α4)3(β2)2 nAChR have potential therapeutic benefits in conditions associated with decline in the output of nAChR in the brain. In previous work, we have studied the pharmacology of the allosteric agonist CMPI (3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)- 1H-pyrazol-4-yl) isoxazole) at the (α4)3(β2)2 nAChR and identified its binding site at the α4:α4 subunit extracellular interface. As part of our ongoing efforts to define structural features that confer CMPI binding selectivity at the α4:α4 interface, we are synthesizing and characterizing the in vitro pharmacology of a series of CMPI analogs using whole-cell current recording from Xenopus laevis oocytes expressing (α4)3(β2)2 nAChR. So far, we synthesized four analogs which have a thiazole (A12a) or imidazole (A12c, A12e, GAT2226) substitution instead of the pyrazole ring found in CMPI. These analogs maintained selectivity for (α4)3(β2)2 over (α4)2(β2)4 nAChR. They did not potentiate (α4)2(β2)3 nAChR when co-applied with either 1 µM or 10 µM ACh and potentiated current induced by 10 µM ACh at the (α4)3(β2)2 nAChR (>4 fold potentiation at 1 µM). The concentration response curve for these analogs is consistent with a rank of potency thiazole

Journal/Conference Details

Presented at the East Texas Research Conference, Tyler, Texas.

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