Phenceptin: a biomimetic model of the phenytoin receptor

Abstract

Can. J. Chem. 66, 2751(1988. 5,s-Diphenylhydanytoin (phenytoin) is the most widely used anticonvulsant drug, but has many side effects. Although its chemical mode of action is unknown, phenytoin is believed to function primarily by interference with the transport of sodium ions across the neuronal membrane. Structure-activity and lipophilicity-activity studies suggest that the drug interacts with its receptor through hydrogen bonding to the N3-C4 amide bond, and an aromatic-aromatic interaction with the C5 substituent. Since sodium channels are cysteine-rich peptides, whose function depends upon the cysteineecystine redox process, it has been hypothesized that the action of the phenytoin receptor may be mimicked by a properly designed cyclodepsipeptide containing a cystinyl moiety, a cavity lined with five oxygen atoms oriented in the trigonal-bipyramidal manner appropriate for selective transport of sodium ions, and a site for the binding of phenytoin. A computer programme and strategy were developed to permit the three-dimensional structures of potential target molecules to be viewed, prior to synthesis. Use of this programme led to the discovery of Boc-~-cystinyl-glycyI-~-prolyl-glycyl-~-prolyl-~-cystine-OCHPh. This compound, termed phenceptin, was synthesized from a linear precursor containing tert-butoxycarbonyl protection at the N-terminus, benzhydryl ester protection at the C-terminus, and trityl protection at sulfur. Detritylation and cyclization to phenceptin were accomplished with iodine in methanol-pyridine. Using an n-octanol membrane to study the kinetics of ion transport, phenceptin was found to transport sodium ions selectively, but only in its oxidized, cyclic form. This transport was inhibited significantly by one mol-equiv. of phenytoin, and not at all by biologically inactive analogs of the drug. The nature of the binding of phenytoin to phenceptin was examined by nuclear magnetic resonance, in n-CsD17-OH solvent, and found to involve hydrogen bonding of the drug to a glycine residue whose oxygen atom is involved in complexation to sodium ions. SAUL WOLFE, RAYMOND JOHN BOWERS, HEE-SOOK SHIN, CHANG-KOOK SOHN, DONALD FREDRIC WEAVER ET KIYULLYANG. Can. J. Chem. 66, 2751 (1988). La diphCnyl-5,s hydantoyne (phtnytoi'ne) est le mtdicament le plus utilist comme anticonvulsivant; toutefois, il provoque de nombreuses rkactions secondaires. MCme si son mode d'action chimique est inconnu, on croit que la phtnytoi'ne agit principalement par interftrence avec le transport des ions sodium a travers les membranes neuronales. Des etudes de structure/activitC et caractere liphophilique/activitt suggkrent que la drogue interagit avec son rtcepteur par le biais de liaisons hydrogknes avec la liaison amide N3-C4 et par une interaction aromatique/aromatique avec le substituant en C5. Puisque les canaux du sodium sont des peptides riches en cysttine dont la fonction dtpend du processus redox cysteine/cystine, il a Ct C suggCrC que l'on pourrait rCpliquer l'action du rCcepteur de la phCnytoi'ne a l'aide d'un cyclod...

Theoretical studies of peptidic structures. Environmental effects

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A Comparison of the CHARMM, AMBER and ECEPP Potentials for Peptides. I. Conformational Predictions for the Tandemly Repeated Peptide (Asn-Ala-Asn-Pro)9

“…Minimization of any of the major published potentials is capable of producing a reasonable approximation to the known conformation of a polypeptide, given a sufficiently close starting point. This is true for fixed geometry (20,21) as well as for flexible geometry (12,22,23). To judge the ability of a potential to predict conformation, it is necessary to compare the conformations obtained by energy minimization from several different starting points, and examine not only the final conformations but also their relative energies (or more accurately, relative statistical weights; see ref.…”

Theoretical conformational analysis of peptides. Evolution of a strategy and its application to cholecystokinin analogs

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