TY - JOUR
T1 - Anticonvulsant effects of bis-1,4-dihydropyridines and the probable role of L-type calcium channels suggested by docking simulations
AU - Ramírez-San Juan, Eduardo
AU - Soriano-Ursúa, Marvin A.
AU - Espinosa-Raya, Judith
AU - Correa-Basurto, José
AU - Trujillo-Ferrara, José G.
AU - Miranda-Ruvalcaba, René
AU - Delgado-Reyes, Francisco
AU - Gómez-Pliego, Raquel
N1 - Publisher Copyright:
© 2014 Springer Science+Business Media New York.
PY - 2014/12
Y1 - 2014/12
N2 - The influx/efflux of calcium (Ca2+) ions through channels in cellular membranes plays a pivotal role in many physiological and physiopathological processes. Among these are those involved in the physiopathology of epileptic seizures. Hence, the control of permeability of ions through these channels is considered a strategy for the development of anticonvulsant drugs. According to the previous reports, dihydropyridine derivatives have proven to be Ca2+ channel blockers and have anticonvulsive properties, presumably by means of their action on L-type Ca2+ channels (LCCs). The aim of the present study was to determine the anticonvulsant effects of four bis-1,4-dihydropyridines (bis-DHPs) in male CF1 mice (25-30 g bw) using two experimental models: maximal electroshock (MES, which induces convulsions with an alternating current of 60 Hz) and pentylenetetrazole administration (PTZ, 90 mg/kg administered i.p.). Additionally, the binding mode was explored with a docking study on a 3-D model of an LCC. The four bis-DHPs herein tested showed a protective effect in relation to the number of convulsions induced by MES, the recovery time after a convulsion, and the duration of the tonic phase. However, only bis-DHPs 01-03 reduced the duration of the clonic phase, and these compounds also produced a significant protective effect against the convulsions induced by PTZ administration. This effect may be related to the interaction of bis-DHPs with a cluster of aromatic residues (Tyr1152, Tyr1463, and Phe1159) involved in blocking calcium flow, as suggested by docking studies.
AB - The influx/efflux of calcium (Ca2+) ions through channels in cellular membranes plays a pivotal role in many physiological and physiopathological processes. Among these are those involved in the physiopathology of epileptic seizures. Hence, the control of permeability of ions through these channels is considered a strategy for the development of anticonvulsant drugs. According to the previous reports, dihydropyridine derivatives have proven to be Ca2+ channel blockers and have anticonvulsive properties, presumably by means of their action on L-type Ca2+ channels (LCCs). The aim of the present study was to determine the anticonvulsant effects of four bis-1,4-dihydropyridines (bis-DHPs) in male CF1 mice (25-30 g bw) using two experimental models: maximal electroshock (MES, which induces convulsions with an alternating current of 60 Hz) and pentylenetetrazole administration (PTZ, 90 mg/kg administered i.p.). Additionally, the binding mode was explored with a docking study on a 3-D model of an LCC. The four bis-DHPs herein tested showed a protective effect in relation to the number of convulsions induced by MES, the recovery time after a convulsion, and the duration of the tonic phase. However, only bis-DHPs 01-03 reduced the duration of the clonic phase, and these compounds also produced a significant protective effect against the convulsions induced by PTZ administration. This effect may be related to the interaction of bis-DHPs with a cluster of aromatic residues (Tyr1152, Tyr1463, and Phe1159) involved in blocking calcium flow, as suggested by docking studies.
KW - Anticonvulsant drugs
KW - Calcium channel antagonists
KW - Dihydropyridine
KW - Docking studies
KW - Epilepsy
KW - Seizures
UR - http://www.scopus.com/inward/record.url?scp=84939882380&partnerID=8YFLogxK
U2 - 10.1007/s00044-014-1083-0
DO - 10.1007/s00044-014-1083-0
M3 - Artículo
SN - 1054-2523
VL - 23
SP - 5149
EP - 5159
JO - Medicinal Chemistry Research
JF - Medicinal Chemistry Research
IS - 12
ER -