Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity

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dc.contributor.author Pereira, Janaina Drawanz [UNIFESP]
dc.contributor.author Caricati-Neto, Afonso [UNIFESP]
dc.contributor.author Miranda-Ferreira, Regiane [UNIFESP]
dc.contributor.author Smaili, Soraya Soubhi [UNIFESP]
dc.contributor.author Godinho, Rosely Oliveira [UNIFESP]
dc.contributor.author los Rios, Cristobal de
dc.contributor.author Leon, Rafael
dc.contributor.author Villaroya, Mercedes
dc.contributor.author Samadi, Abdelouahid
dc.contributor.author Marco-Contelles, Jose
dc.contributor.author Jurkiewicz, Neide Hyppolito [UNIFESP]
dc.contributor.author Garcia, Antonio G.
dc.contributor.author Jurkiewicz, Aron [UNIFESP]
dc.date.accessioned 2016-01-24T14:16:53Z
dc.date.available 2016-01-24T14:16:53Z
dc.date.issued 2011-06-25
dc.identifier http://dx.doi.org/10.1016/j.ejphar.2011.03.042
dc.identifier.citation European Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 660, n. 2-3, p. 411-419, 2011.
dc.identifier.issn 0014-2999
dc.identifier.uri http://repositorio.unifesp.br/handle/11600/33806
dc.description.abstract We have recently synthesized a new series of hybrid compounds having the moieties of tacrine, a potent inhibitor of brain and peripheral acetylcholinesterase (AChE), and nimodipine, a blocker of L-type voltage-dependent calcium channels (VDCCs). These compounds were designed to target AChE and L calcium channels in the brain, as potential therapeutic agents in Alzheimer's disease. We performed the present study to determine the main peripheral side effects of two of these compounds, ITH12117 and ITH12118. We have here shown that in rat vas deferens these compounds inhibited AChE with a potency about 1000-fold lower than that of physostigmine or tacrine. Furthermore, the hybrid compounds enhanced contractions evoked by acetylcholine, with a potency about 100-fold lower than that of physostigmine or tacrine. Additionally, contractions induced by Ca2+ on depolarized vas deferens were blocked by nimodipine with greater efficacy, compared with ITH12117 and ITH12118. Compound ITH12118 (1 mu M) caused a pronounced inhibition of the tonic (but not phasic) contraction elicited by electrical field stimulation. Furthermore, the same dose of nimodipine and ITH12118 blocked by 75% cytosolic Ca2+ elevations produced by acetylcholine, noradrenaline, or ATP. As a matter of comparison, we showed that rat brain cortex AChE was inhibited by ITH12118 with a potency 10 to 20-fold higher than that for vas deferens. This study shows that ITH12118 could be a paradigmatic multitarget compound having selective brain effects with smaller peripheral side effects. This may help to orient the search of new neuroprotective compounds with potential therapeutic application in Alzheimer's disease. (C) 2011 Elsevier B.V. All rights reserved. en
dc.description.sponsorship Governments of Spain and Brazil
dc.description.sponsorship Convenio de Colaboracion Universidad Autonoma de Madrid-Escola Paulista de Medicina-UNIFESP
dc.description.sponsorship Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorship Cooperacion Universitaria UAM - Santander con America Latina
dc.description.sponsorship C.I.E.N.
dc.description.sponsorship Agencia Lain Entalgo
dc.description.sponsorship MICINN
dc.format.extent 411-419
dc.language.iso eng
dc.publisher Elsevier B.V.
dc.relation.ispartof European Journal of Pharmacology
dc.rights Acesso restrito
dc.subject Cholinesterase blocker en
dc.subject Calcium channel blocker en
dc.subject Rat vas deferens en
dc.subject Rat brain cortex en
dc.subject Hybrid antagonist en
dc.subject Alzheimer's disease en
dc.subject Tacripyrines en
dc.subject ITH12117 en
dc.subject ITH12118 en
dc.subject Acetylcholinesterase en
dc.subject Calcium signaling en
dc.title Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity en
dc.type Artigo
dc.rights.license http://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.contributor.institution Universidade Federal de São Paulo (UNIFESP)
dc.contributor.institution Univ Autonoma Madrid
dc.contributor.institution Hosp Univ Princesa
dc.contributor.institution CSIC
dc.contributor.institution Univ Cambridge
dc.description.affiliation Universidade Federal de São Paulo, Dept Pharmacol, BR-04044020 São Paulo, Brazil
dc.description.affiliation Univ Autonoma Madrid, Inst Teofilo Hernando, Madrid 28029, Spain
dc.description.affiliation Univ Autonoma Madrid, Fac Med, Dept Farmacol & Terapeut, E-28029 Madrid, Spain
dc.description.affiliation Hosp Univ Princesa, Serv Farmacol Clin, Madrid 28006, Spain
dc.description.affiliation CSIC, Ctr Nacl Quim Organ, Madrid, Spain
dc.description.affiliation Univ Cambridge, Cambridge CB2 1TN, England
dc.description.affiliationUnifesp Universidade Federal de São Paulo, Dept Pharmacol, BR-04044020 São Paulo, Brazil
dc.description.sponsorshipID Governments of Spain and Brazil: PHB 2005-0018-PC
dc.description.sponsorshipID C.I.E.N.: ISCIII P5016/09
dc.description.sponsorshipID Agencia Lain Entalgo: CM-NDE.07/09
dc.description.sponsorshipID MICINN: 2010S-SAL-0255-20096
dc.description.sponsorshipID : CM S-SAL-0275
dc.description.sponsorshipID : RENEVAS ISC III R006/0026/0009
dc.identifier.doi 10.1016/j.ejphar.2011.03.042
dc.description.source Web of Science
dc.identifier.wos WOS:000291623600024


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