Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B

Aim: Alpha7-nicotinic acetylcholine receptor (alpha 7 nAChR) is a ligand-gated Ca2+-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of alpha 7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel alpha 7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates alpha 7 nAChR. Methods: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human alpha 7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of alpha 7 nAChR by Br-IQ17B. Results: Br-IQ17B potently activates alpha 7 nAChR with an EC50 of 1.8 +/- 0.2 mu mol/L. Br-IQ17B is selective over other subtypes such as alpha 4 beta 2 and alpha 3 beta 4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the alpha 7 blocker [H-3]-MLA to hippocampal crude membranes with a K-i of 14.9 +/- 3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked alpha 7-like currents that were inhibited by MLA and enhanced in the presence of the alpha 7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. Conclusion: We identified the novel, potent, and selective alpha 7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of alpha 7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.