STRUCTURAL DEPENDENCE OF THE ALLOSTERIC INTERACTION OF SEMIRIGID VERAPAMIL ANALOGS WITH DIHYDROPYRIDINE-BINDING IN KITTEN HEART

Structural determinants of the allosteric interaction of semi-rigid ve rapamil analogues with dihydropyridine binding were investigated in ki tten heart using [H-3](+)-isradipine as radioligand, Chemical variatio ns were performed in the alkyl chain of verapamil and include introduc tion of unsaturation (double or triple bonds) or the insertion of cycl ohexyl moieties. Introduction of unsaturation generally reduces the al losteric interaction in the case of 'double bond' - and abolishes it i n the case of 'triple bond' - derivatives. Also the introduction of cy clohexyl moieties diminishes the potency of allosteric interaction: de rivatives with the phenylethylamino side chain in an equatorial positi on exhibit the allosteric interaction, while it is lacking in derivati ves with the basic side chain in axial position. Thus, the reduced con formational flexibility of the new verapamil congeners reduces or abol ishes their ability to allosterically interfere with dihydropyridine b inding. A molecular interpretation was approached by molecular modelli ng studies. The strategy was to find low energy conformations common t o the active congeners, but not shared by the inactive ones. Structura l features discriminating allosterically active and inactive congeners comprise: 1) the position of the nitrogen, 2) the volume occupied by the N-methyl groups, 3) the direction of the N-H bond and 4) the posit ion of the phenyl ring in the basic side chain.