N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists

Manuel Criado, José Mulet, Francisco Sala, Salvador Sala, Inés Colmena, Luis Gandía, Oscar M. Bautista-Aguilera, Abdelouahid Samadi, Mourad Chioua, José Marco-Contelles

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1157-1165
Number of pages9
JournalACS Chemical Neuroscience
Issue number8
Publication statusPublished - Aug 17 2016
Externally publishedYes


  • Nicotinic receptors
  • blockers
  • piperidine derivatives
  • α7, ionic currents

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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