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

Janaína Drawanz Pereira, Afonso Caricati-Neto, Regiane Miranda-Ferreira, Soraya Shoubi Smaili, Rosely Oliveira Godinho, Cristobal De Los Rios, Rafael Léon, Mercedes Villaroya, Abdelouahid Samadi, José Marco-Contelles, Neide Hyppolito Jurkiewicz, Antonio G. Garcia, Aron Jurkiewicz

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)


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 μM) 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.

Original languageEnglish
Pages (from-to)411-419
Number of pages9
JournalEuropean Journal of Pharmacology
Issue number2-3
Publication statusPublished - Jun 25 2011
Externally publishedYes


  • Acetylcholinesterase
  • Alzheimer's disease
  • Calcium channel blocker
  • Calcium signaling
  • Cholinesterase blocker
  • Hybrid antagonist
  • ITH12117
  • ITH12118
  • Rat brain cortex
  • Rat vas deferens
  • Tacripyrines

ASJC Scopus subject areas

  • Pharmacology


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