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

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

Author Pereira, Janaina Drawanz Autor UNIFESP Google Scholar
Caricati-Neto, Afonso Autor UNIFESP Google Scholar
Miranda-Ferreira, Regiane Autor UNIFESP Google Scholar
Smaili, Soraya Soubhi Autor UNIFESP Google Scholar
Godinho, Rosely Oliveira Autor UNIFESP Google Scholar
los Rios, Cristobal de Google Scholar
Leon, Rafael Google Scholar
Villaroya, Mercedes Google Scholar
Samadi, Abdelouahid Google Scholar
Marco-Contelles, Jose Google Scholar
Jurkiewicz, Neide Hyppolito Autor UNIFESP Google Scholar
Garcia, Antonio G. Google Scholar
Jurkiewicz, Aron Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Univ Autonoma Madrid
Hosp Univ Princesa
Univ Cambridge
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.
Keywords Cholinesterase blocker
Calcium channel blocker
Rat vas deferens
Rat brain cortex
Hybrid antagonist
Alzheimer's disease
Calcium signaling
Language English
Sponsor Governments of Spain and Brazil
Convenio de Colaboracion Universidad Autonoma de Madrid-Escola Paulista de Medicina-UNIFESP
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Cooperacion Universitaria UAM - Santander con America Latina
Agencia Lain Entalgo
Grant number Governments of Spain and Brazil: PHB 2005-0018-PC
C.I.E.N.: ISCIII P5016/09
Agencia Lain Entalgo: CM-NDE.07/09
MICINN: 2010S-SAL-0255-20096
: CM S-SAL-0275
: RENEVAS ISC III R006/0026/0009
Date 2011-06-25
Published in European Journal of Pharmacology. Amsterdam: Elsevier B.V., v. 660, n. 2-3, p. 411-419, 2011.
ISSN 0014-2999 (Sherpa/Romeo, impact factor)
Publisher Elsevier B.V.
Extent 411-419
Origin http://dx.doi.org/10.1016/j.ejphar.2011.03.042
Access rights Closed access
Type Article
Web of Science ID WOS:000291623600024
URI http://repositorio.unifesp.br/handle/11600/33806

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