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

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dc.contributor.authorPereira, Janaina Drawanz [UNIFESP]
dc.contributor.authorCaricati-Neto, Afonso [UNIFESP]
dc.contributor.authorMiranda-Ferreira, Regiane [UNIFESP]
dc.contributor.authorSmaili, Soraya Soubhi [UNIFESP]
dc.contributor.authorGodinho, Rosely Oliveira [UNIFESP]
dc.contributor.authorlos Rios, Cristobal de
dc.contributor.authorLeon, Rafael
dc.contributor.authorVillaroya, Mercedes
dc.contributor.authorSamadi, Abdelouahid
dc.contributor.authorMarco-Contelles, Jose
dc.contributor.authorJurkiewicz, Neide Hyppolito [UNIFESP]
dc.contributor.authorGarcia, Antonio G.
dc.contributor.authorJurkiewicz, Aron [UNIFESP]
dc.contributor.institutionUniversidade Federal de São Paulo (UNIFESP)
dc.contributor.institutionUniv Autonoma Madrid
dc.contributor.institutionHosp Univ Princesa
dc.contributor.institutionCSIC
dc.contributor.institutionUniv Cambridge
dc.date.accessioned2016-01-24T14:16:53Z
dc.date.available2016-01-24T14:16:53Z
dc.date.issued2011-06-25
dc.description.abstractWe 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.affiliationUniversidade Federal de São Paulo, Dept Pharmacol, BR-04044020 São Paulo, Brazil
dc.description.affiliationUniv Autonoma Madrid, Inst Teofilo Hernando, Madrid 28029, Spain
dc.description.affiliationUniv Autonoma Madrid, Fac Med, Dept Farmacol & Terapeut, E-28029 Madrid, Spain
dc.description.affiliationHosp Univ Princesa, Serv Farmacol Clin, Madrid 28006, Spain
dc.description.affiliationCSIC, Ctr Nacl Quim Organ, Madrid, Spain
dc.description.affiliationUniv Cambridge, Cambridge CB2 1TN, England
dc.description.affiliationUnifespUniversidade Federal de São Paulo, Dept Pharmacol, BR-04044020 São Paulo, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipGovernments of Spain and Brazil
dc.description.sponsorshipConvenio de Colaboracion Universidad Autonoma de Madrid-Escola Paulista de Medicina-UNIFESP
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipCooperacion Universitaria UAM - Santander con America Latina
dc.description.sponsorshipC.I.E.N.
dc.description.sponsorshipAgencia Lain Entalgo
dc.description.sponsorshipMICINN
dc.description.sponsorshipIDGovernments of Spain and Brazil: PHB 2005-0018-PC
dc.description.sponsorshipIDC.I.E.N.: ISCIII P5016/09
dc.description.sponsorshipIDAgencia Lain Entalgo: CM-NDE.07/09
dc.description.sponsorshipIDMICINN: 2010S-SAL-0255-20096
dc.description.sponsorshipID: CM S-SAL-0275
dc.description.sponsorshipID: RENEVAS ISC III R006/0026/0009
dc.format.extent411-419
dc.identifierhttp://dx.doi.org/10.1016/j.ejphar.2011.03.042
dc.identifier.citationEuropean Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 660, n. 2-3, p. 411-419, 2011.
dc.identifier.doi10.1016/j.ejphar.2011.03.042
dc.identifier.issn0014-2999
dc.identifier.urihttp://repositorio.unifesp.br/handle/11600/33806
dc.identifier.wosWOS:000291623600024
dc.language.isoeng
dc.publisherElsevier B.V.
dc.relation.ispartofEuropean Journal of Pharmacology
dc.rightsinfo:eu-repo/semantics/restrictedAccess
dc.rights.licensehttp://www.elsevier.com/about/open-access/open-access-policies/article-posting-policy
dc.subjectCholinesterase blockeren
dc.subjectCalcium channel blockeren
dc.subjectRat vas deferensen
dc.subjectRat brain cortexen
dc.subjectHybrid antagonisten
dc.subjectAlzheimer's diseaseen
dc.subjectTacripyrinesen
dc.subjectITH12117en
dc.subjectITH12118en
dc.subjectAcetylcholinesteraseen
dc.subjectCalcium signalingen
dc.titleEffects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activityen
dc.typeinfo:eu-repo/semantics/article
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