MOLECULAR MODELING OF (E)-1-ALKYL-4(3)-[2-(1H-AZOLYL)VINYL]-PYRIDINIUM SALTS AND EVALUATION OF THEIR BEHAVIOR TOWARDS CHOLINE-ACETYLTRANSFERASE

A new type of extended pi-system aza-analogue of (E)-4-[2-(1-naphthylv inyl)]-1-substituted pyridinium salts (NVP+) has been designed and its inhibitory activity towards choline acetyltransferase (ChAT) has been evaluated in vitro. Among the several examples of the title quaternar y salts synthesized 2 and 3, the indolylvinylpyridinium salt 2e is the only one to show a very low ChAT inhibition. The molecular modeling s tudy is highly illustrative of their behavior towards ChAT and interac tion with the recognition site. Thus, several selected cations togethe r with the reference NVP+ compound la were studied at the PM3 and AM1 levels respectively. At the global minima, all the compounds are plana r, which, from the electron charge distribution, shows a degree of pol arization similar to the NVP+ model compound la. However, the fitting of all optimized structures indicated that only the indole derivative 2e showed the same aromatic fragment orientation as la, which allows u s to define a volume that is not accessible to ligands in the enzyme a nd consequently to a refined model of the choline acetyltransferase re cognition site. (C) 1997 Elsevier Science Ltd.