[Productive conformations of ligands and topography of the alpha1-adrenoreceptor active site based on theoretical...

Theoretical conformational analysis of a series of alpha 1-adrenoceptor activators and inhibitors including 6-fluoronoradrenaline, methoxamine, phenoxydenzamine, piperoxane, and WB-4101 has been carried out by classical semi-empirical method. The conformational energy minimization was performed in the space of the majority of torsional and bond angles. The selection of productive conformations was made according to the following criteria: 1) low conformational energy; 2) similarity of the nitrogen atoms and phenyl rings spatial disposition in all ligands; 3) accessibility for intermolecular interactions of the functional moieties in all ligands. The productive conformation of alpha 1-adrenoceptor endogenous activator, noradrenaline, has the Ph-C-C-N fragment in the perpendicular (-)-gaushe conformation, and ethanolamine side chain beta-hydroxyl in trans arrangement relative to the meta hydroxyl of the catechol ring. A topographic model for the receptor was suggested, its components being the arylophilic, nucleophilic, hydrophobic, and proton acceptor groups, along with the binding region for catechol hydroxyls, situated against the most accessible sides of the functional moieties of the ligands. Structure-activity relationships for a series of alpha 1-adrenoceptor ligands are discussed in the light of the proposed model. Both common and characteristic features of the alpha 1-adrenoceptor model are considered in comparison with the earlier suggested beta 2-adrenoceptor model.