TY - JOUR
T1 - N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists
AU - Criado, Manuel
AU - Mulet, José
AU - Sala, Francisco
AU - Sala, Salvador
AU - Colmena, Inés
AU - Gandía, Luis
AU - Bautista-Aguilera, Oscar M.
AU - Samadi, Abdelouahid
AU - Chioua, Mourad
AU - Marco-Contelles, José
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/8/17
Y1 - 2016/8/17
N2 - 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.
AB - 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.
KW - Nicotinic receptors
KW - blockers
KW - piperidine derivatives
KW - α7, ionic currents
UR - http://www.scopus.com/inward/record.url?scp=84983460880&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983460880&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.6b00122
DO - 10.1021/acschemneuro.6b00122
M3 - Article
C2 - 27254782
AN - SCOPUS:84983460880
SN - 1948-7193
VL - 7
SP - 1157
EP - 1165
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 8
ER -