Theoretical studies applicable to the design of novel anticonvulsants: an AM1 molecular orbital structure-activity study of dihydropyridine calcium channel antagonists

The development and synthesis of anticonvulsant new chemical entities that are distinct from the cyclic ureides in current clinical use is a continuing neuropharmacologic priority. The design of neuronal specific dihydropyridines active at the L-type calcium channel protein represents a rational app...

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Veröffentlicht in:Canadian journal of chemistry 1992-09, Vol.70 (9), p.2449-2460
Hauptverfasser: Bikker, Jack Andrew, Weaver, Donald Fredric
Format: Artikel
Sprache:eng
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Zusammenfassung:The development and synthesis of anticonvulsant new chemical entities that are distinct from the cyclic ureides in current clinical use is a continuing neuropharmacologic priority. The design of neuronal specific dihydropyridines active at the L-type calcium channel protein represents a rational approach to this design problem. To provide the structural data required for the design of anticonvulsant dihydropyridines, an AM1 semi-empirical molecular orbital study has been undertaken. Forty-six dihydropyridine calcium channel antagonists have been fully optimized at the AM1 level. Each of the 46 analogues was considered in six conformations to provide a systematic evaluation of changes in ester and phenyl ring orientation. The calculational validity of the AM1 Hamiltonian when applied to dihydropyridines was demonstrated by comparing AM1-optimized structures to experimental (X-ray crystallographic) and abinitio molecular orbital (STO 3G basis set) geometries. For each dihydropyridine, 79 AM1-derived geometric and electronic descriptors were obtained. The resulting descriptor matrix comparing structural descriptors with biological activity was statistically reduced to provide regression and discriminant structure-activity models for dihydropyridine calcium channel antagonism.
ISSN:0008-4042
1480-3291
DOI:10.1139/v92-310