4.6 Article

N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

期刊

ACS CHEMICAL NEUROSCIENCE
卷 7, 期 8, 页码 1157-1165

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00122

关键词

Nicotinic receptors; piperidine derivatives; alpha 7; ionic currents; blockers

资金

  1. Spanish Ion Channel Initiative-CONSOLIDER INGENIO [SAF2011-22802, SAF2012-33304, CSD2008-00005]
  2. Spanish Ministry of Science and Innovation (Ministerio de Economia y Competitividad)

向作者/读者索取更多资源

A series of multitarget directed propargylamines, as well as other differently susbstituted piperidines have been screened as potential modulators of neuronal nicotinic acetylcholine receptors (nAChRs). Most of them showed antagonist actions on alpha 7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric alpha 7 nAChRs, whereas they were less effective on heteromeric alpha 3 beta 4 and alpha 4 beta 2 nAChRs (up to 20-fold higher IC50 values in the case of 13). Antagonism was concentration dependent and noncompetitive, suggesting that these compounds behave as negative allosteric modulators of nAChRs. Upon the study of a series of less complex derivatives, the N-benzylpiperidine motif, common to these compounds, was found to be the main pharmacophoric group. Thus, 2-(1-benzylpiperidin-4-yl)-ethylamine (48) showed an inhibitory potency comparable to the one of the previous compounds and also a clear preference for alpha 7 nAChRs. In a neuroblastoma cell line, representative compounds 13 and 48 also inhibited, in a concentration-dependent manner, cytosolic Ca2+ signals mediated by nAChRs. Finally, compounds 38 and 13 inhibited 5-HT3A serotonin receptors whereas they had no effect on alpha 1 glycine receptors. Given the multifactorial nature of many pathologies in which nAChRs are involved, these piperidine antagonists could have a therapeutic potential in cases where cholinergic activity has to be negatively modulated.

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