title: N-Benzylpiperidine Derivatives as α7 Nicotinic Receptor Antagonists.
abstract: 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 Ca(2+) 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.
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC , Sant Joan d'Alacant, 03550-Alicante, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Criado
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC , Sant Joan d'Alacant, 03550-Alicante, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Mulet
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC , Sant Joan d'Alacant, 03550-Alicante, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sala
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC , Sant Joan d'Alacant, 03550-Alicante, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Sala
authors.affiliation: Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029-Madrid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Colmena
authors.affiliation: Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid , C/Arzobispo Morcillo 4, 28029-Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Gandía
authors.affiliation: Instituto de Quimica Orgánica General, Laboratory of Medicinal Chemistry, Consejo Superior de Investigaciones Científicas , C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Bautista-Aguilera
authors.affiliation: Instituto de Quimica Orgánica General, Laboratory of Medicinal Chemistry, Consejo Superior de Investigaciones Científicas , C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.affiliation: Instituto de Quimica Orgánica General, Laboratory of Medicinal Chemistry, Consejo Superior de Investigaciones Científicas , C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Mourad
authors.initials: M
authors.lastname: Chioua
authors.affiliation: Instituto de Quimica Orgánica General, Laboratory of Medicinal Chemistry, Consejo Superior de Investigaciones Científicas , C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D008845:Microinjections; D009447:Neuroblastoma / Q000473:pathology; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; D007555:Isoxazoles; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010671:Phenylurea Compounds; D010880:Piperidines; D011978:Receptors, Nicotinic; D044406:Receptors, Serotonin, 5-HT3; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D012701:Serotonin; C071293:1-benzylpiperidine; D000109:Acetylcholine; D002118:Calcium
keywords: Nicotinic receptors; blockers; piperidine derivatives; α7, ionic currents