TY - JOUR
T1 - Effects of novel tacripyrines ITH12117 and ITH12118 on rat vas deferens contractions, calcium transients and cholinesterase activity
AU - Pereira, Janaína Drawanz
AU - Caricati-Neto, Afonso
AU - Miranda-Ferreira, Regiane
AU - Smaili, Soraya Shoubi
AU - Godinho, Rosely Oliveira
AU - Rios, Cristobal De Los
AU - Léon, Rafael
AU - Villaroya, Mercedes
AU - Samadi, Abdelouahid
AU - Marco-Contelles, José
AU - Jurkiewicz, Neide Hyppolito
AU - Garcia, Antonio G.
AU - Jurkiewicz, Aron
N1 - Funding Information:
This work was supported by a collaborative exchange research grant between the Governments of Spain and Brazil (grant PHB 2005–0018—PC ); by “ Convenio de Colaboración Universidad Autonoma de Madrid — Escola Paulista de Medicina-UNIFESP ”, by Capes, Brazil, to AJ, and grant from “ Cooperación Universitaria UAM — Santander con América Latina ”. Supported also by CM S-SAL-0275 and RENEVAS ISC III R006/0026/0009 , to AGG and JMC, as well as by the following grants to AGG: (1) Fundación C.I.E.N. ISCIII P5016/09 ; (2) Agencia Laín Entalgo CM-NDE.07/09 ; and (3) MICINN Consolider 2010S-SAL-0255-20096 .
PY - 2011/6/25
Y1 - 2011/6/25
N2 - 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.
AB - 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.
KW - Acetylcholinesterase
KW - Alzheimer's disease
KW - Calcium channel blocker
KW - Calcium signaling
KW - Cholinesterase blocker
KW - Hybrid antagonist
KW - ITH12117
KW - ITH12118
KW - Rat brain cortex
KW - Rat vas deferens
KW - Tacripyrines
UR - http://www.scopus.com/inward/record.url?scp=79956086520&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79956086520&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2011.03.042
DO - 10.1016/j.ejphar.2011.03.042
M3 - Article
C2 - 21497158
AN - SCOPUS:79956086520
SN - 0014-2999
VL - 660
SP - 411
EP - 419
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 2-3
ER -