Yao Xue Xue Bao 2016 Oct 01;5110:1584-94.

[The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold].

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Alpha7 nicotinic acetylcholine receptor（α7 nAChR） is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships（SAR）. All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16 c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60 ± 0.19 μmol·L-1 and maximum effect (Emax) of 69.0% ± 2.8% compared with 3 mmol·L-1 ACh. Compound 17 b with 8-cyclopropyl substitution shows an increased Emax of 81.1% ± 9.3% with EC50 at 2.74 ± 0.74 μmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.

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