title: Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity.
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 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.
authors.affiliation: Department of Pharmacology, Federal University of São Paulo, 04044-020 São Paulo, Brazil.
authors.forename: Janaína Drawanz
authors.initials: JD
authors.lastname: Pereira
authors.forename: Afonso
authors.initials: A
authors.lastname: Caricati-Neto
authors.forename: Regiane
authors.initials: R
authors.lastname: Miranda-Ferreira
authors.forename: Soraya Shoubi
authors.initials: SS
authors.lastname: Smaili
authors.forename: Rosely Oliveira
authors.initials: RO
authors.lastname: Godinho
authors.forename: Cristobal
authors.initials: C
authors.lastname: de los Rios
authors.forename: Rafael
authors.initials: R
authors.lastname: Léon
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villaroya
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.forename: Neide Hyppolito
authors.initials: NH
authors.lastname: Jurkiewicz
authors.forename: Antonio G
authors.initials: AG
authors.lastname: Garcia
authors.forename: Aron
authors.initials: A
authors.lastname: Jurkiewicz
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000110:Acetylcholinesterase / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004558:Electric Stimulation; D016257:Fura-2 / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009553:Nimodipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000494:pharmacology*; D014649:Vas Deferens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology*
chemical_list: D002800:Cholinesterase Inhibitors; D013619:Tacrine; D009553:Nimodipine; D000255:Adenosine Triphosphate; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D000109:Acetylcholine; D002118:Calcium; D016257:Fura-2; D009638:Norepinephrine