SYNTHESIS AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF A NOVELSERIES OF SMALL-CONDUCTANCE CA2-ACTIVATED K+ CHANNEL BLOCKERS RELATEDTO DEQUALINIUM()

The synthesis, pharmacological testing, and quantitative structure-act ivity relationship studies of a novel series of bisquinolinium small c onductance Ca2+-activated K+ channel blockers (23) related to dequalin ium are described. In this series, two quinolinium rings are linked vi a the 4-position to an alpha,omega-diamino alkylene chain and the ring N atom is quaternized with a methyl or benzyl group. The exocyclic N atom can be replaced by O, S, or CH2 but with some loss of potency. Th e quinoline groups do not have to be quaternized for blocking activity , as long as they are basic enough to be protonated at the site of act ion. For the quaternary compounds, there is considerable steric tolera nce for the group R attached to the ring N atom of the quinoline; a be nzyl group gave the optimum potency in this series. Moreover, and in c ontrast to previously reported results for dequalinium analogues, ther e is no correlation of activity with N-1 charge or E(HOMO). On the oth er hand, a good correlation was obtained between the blocking potency of the compounds and E(LUMO) [pEMR = 1.16(+/-0.26)E(LUMO) + 5.33(+/-1. 29) (n = 11, r = 0.83, s = 0.243)]. It has been possible to combine th is equation with the previously reported E(LUMO) correlation for a ser ies of dequalinium analogues to include all the compounds of both seri es [pEMR = 1.17(+/-0.15)E(LUMO) + 5.33(+/-0.76) (n = 24, r = 0.85, s = 0.249)]. A possible physical meaning for the E(LUMO) correlation base d upon the principle of maximum hardness is discussed.