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1 The normal and a mutant (S248F) human neuronal α4β2 nicotinic receptors, and their interaction with the channel blocker carbamazepine (CBZ) have been modelled. The mutant, responsible for the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), has an enhanced sensitivity to and a slower recovery from desensitization, a lower conductance, short open times, reduced calcium permeability, and is 3 fold more sensitive to CBZ, a drug used in the treatment of partial epilepsies. 2 Mutant channel properties are explained by the physicochemical properties of the two Phe248 side chains, including size and cation-π interaction, and their dynamic behaviour. A defective mechanism of dehydration might be responsible for the reduced calcium influx. 3 Phe248 residues are the main component of CBZ binding sites in the mutant, while this is not true for Ser248 in the normal receptor. 4 A higher number of blocking binding sites and a predicted higher affinity found for CBZ in the mutant account for its differential sensitivity to CBZ. 5 Aromatic-aromatic interactions between CBZ and the two Phe248 account for the difference in affinity, which is at least 12 times higher for the mutant, depending on the method used for calculating Ki. 6 Normal vs mutant differences in Ki, enhanced by the higher number of blocking binding sites in the mutant, seem excessive compared to the differential sensitivities to CBZ experimentally found. The negative cooperativity suggested by a predicted overlapping of blocking and non-blocking binding sites gives an explanation, as overlapping is higher in the mutant. 7 For both types of receptors we found that the carbamyl group of the best blocking conformers of CBZ forms hydrogen bonds with serine residues, which may explain the fundamental role of that moiety for this molecule to act as antiepileptic drug.


Documento: Artículo
Título:Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy
Autor:Ortells, M.O.; Barrantes, G.E.
Filiación:Inst. de Neurociencia (UBA-CONICET), Fac. de Cs. Ex. y Nat, Cdad. Univ., 1428 Buenos Aires, Argentina
Palabras clave:Carbamazepine; Epilepsy; Molecular modelling; Nicotinic receptor; anticonvulsive agent; carbamazepine; functional group; mutant protein; nicotinic receptor; serine; anticonvulsive agent; carbamazepine; nicotinic receptor alpha4beta2; article; autosomal dominant disorder; binding affinity; calcium transport; dehydration; drug binding site; drug receptor binding; frontal lobe epilepsy; hydrogen bond; molecular model; molecular size; physical chemistry; prediction; priority journal; structure activity relation; chemical structure; chemistry; dominant gene; genetics; human; metabolism; mutation; Anticonvulsants; Carbamazepine; Epilepsy, Frontal Lobe; Genes, Dominant; Human; Models, Molecular; Mutation; Receptors, Nicotinic; Support, Non-U.S. Gov't; Anticonvulsants; Carbamazepine; Epilepsy, Frontal Lobe; Humans; Receptors, Nicotinic
Página de inicio:883
Página de fin:895
Título revista:British Journal of Pharmacology
Título revista abreviado:Br. J. Pharmacol.
CAS:carbamazepine, 298-46-4, 8047-84-5; serine, 56-45-1, 6898-95-9; Anticonvulsants; Carbamazepine, 298-46-4; Receptors, Nicotinic; nicotinic receptor alpha4beta2


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---------- APA ----------
Ortells, M.O. & Barrantes, G.E. (2002) . Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy. British Journal of Pharmacology, 136(6), 883-895.
---------- CHICAGO ----------
Ortells, M.O., Barrantes, G.E. "Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy" . British Journal of Pharmacology 136, no. 6 (2002) : 883-895.
---------- MLA ----------
Ortells, M.O., Barrantes, G.E. "Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy" . British Journal of Pharmacology, vol. 136, no. 6, 2002, pp. 883-895.
---------- VANCOUVER ----------
Ortells, M.O., Barrantes, G.E. Molecular modelling of the interactions of carbamazepine and a nicotinic receptor involved in the autosomal dominant nocturnal frontal lobe epilepsy. Br. J. Pharmacol. 2002;136(6):883-895.