N-benzylpiperidine derivatives as α7 nicotinic receptor antagonists
EntityUAM. Departamento de Farmacología
PublisherAmerican Chemical Society
10.1021/acschemneuro.6b00122ACS Chemical Neuroscience 7.8 (2016): 1157–1165
Funded byThis work was supported by grants SAF2011-22802 to S.S., SAF2012-33304 to J.M.-C., CSD2008-00005 (the Spanish Ion Channel Initiative-CONSOLIDER INGENIO 2010) to M.C. from the Spanish Ministry of Science and Innovation (Ministerio de Economía y Competitividad).
ProjectGobierno de España. SAF2011-22802; Gobierno de España. SAF2012-33304; Gobierno de España. CSD2008-00005
SubjectsBlockers; Nicotinic receptors; Piperidine derivatives; α7, ionic currents; Farmacia
NoteThis document is the accepted manuscript version of a Published Work that appeared in final form in ACS Chemical Neuroscience 7.8, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see DOI: 10.1021/acschemneuro.6b00122
Rights© 2016 American Chemical Society
.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 α7 nAChRs. Especially, compounds 13, 26, and 38 displayed submicromolar IC50 values on homomeric α7 nAChRs, whereas they were less effective on heteromeric α3β4 and α4β2 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 α7 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 α1 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.
Google Scholar:Criado, Manuel - Mulet, José - Sala, Francisco - Sala, Salvador - Colmena, Inés - Gandía, Luis - Bautista-Aguilera, Óscar M. - Samadi, Abdelouahid - Chioua, Mourad - Marco-Contelles, José
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