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

Abstract

Can. J. Chem. 70, 2449 (1992. 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 AM l-optimized structures to experimental (X-ray crystallographic) and nb initio molecular orbital (ST0 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.JACK ANDREW BIKKER et DONALD FREDRIC WEAVER. Can. J. Chem. 70, 2449 (1992). Le developpement et la synthkse de nouvelles entitCs chimiques anticonvulsives distinctes des urCides cycliques actuellement en usage clinique sont des priorites neuropharmacologiques permanentes. La conception de dihydropyridines de specificit6 neuronale, actives au niveau de la protkine de type L du canal du calcium, reprCsente une approche rationnelle a ce problkme. Afin d'obtenir les donnCes structurales necessaires pour la conception de dihydropyridines anticonvulsives, on a entrepris une etude d'orbitales molCculaires semi-empiriques AMI. OpCrant au niveau AMI, on a optimisC 46 dihydropyridines antagonistes du canal du calcium. Afin d'obtenir une &valuation systkmatique des changements dans I'orientation de I'ester et du noyau phCnyle, on a considCrC chacun de ces 46 analogues dans six conformations. On a dCmontrC que I'hamiltonien AM1 applique aux dihydropyridines est valide pour les calculs en procCdant a une comparaison des structures optimisees par AM1 avec celles obtenues expCrimentalement (diffraction des rayons X) et avec les gComCtries obtenues par des calculs d'orbitales niolCculaires ah irzitio (base S T 0 3G). Pour chaque dihydropyridine, on a obtenu 79 descripteurs gComCtriques et Clectroniques derivCs du AMI. On a reduit statistiquement la matrice resultante de descripteurs comparant les descripteurs structuraux avec I'activite biologique afin d'obtenir des modkles de regression et d'activitC-structure discriminatoires pour la dihydropyridine antagoniste du canal du calcium.[Traduit par la redaction]

Review, reevaluation, and new results in quantitative structure-activity studies of anticonvulsants

“…(20) was reported 20 (Tables I, II). Bikker and Weaver 22 in an extensive AM-1 molecular orbital structure-activity study of dihydro-pyridine (DHP, calcium channel antagonists) tried to apply theoretical studies to the design of (Table III). These data were acquired measuring the inhibition of smooth muscle contraction by calcium channel blockade.…”