Structural modifications of benzanilide derivatives, effective potassium channel openers. X.

Large-conductance calcium-activated potassium (BK) channels are involved in many fundamental cell functions. Consistently, the ability to activate BK channels by exogenous compounds is considered as a promising pharmacodynamic pattern for the potential treatment of several pathologies. In this perspective, the development of new and selective BK-openers can be considered as an actual field of research. This paper reports the synthesis and pharmacological evaluation of new benzanilides, useful for deepening the comprehension of the structure-activity relationships, emerged in previous studies on this class of BK-activators. From a structural point of view, these benzanilides belong to a general class of BK-activators, showing a common pharmacophoric model, consisting of two aryl groups linked through an appropriate "spacer" and the almost obligatory presence of a phenolic hydroxyl. In particular, a new series of benzanilides, in which the phenyl rings have been widely changed both on the acidic portion and the basic one of the amide spacer, were synthesised. Their vasorelaxing effects, induced through the activation of BK channels, were also evaluated. Although many compounds exhibited effects which could not be attributed to the activation of BK channels, two derivatives showed a clear profile of BK-activators with vasodilator activity comparable to or slightly lower than that recorded for the reference benzimidazolone NS1619. A further molecular modelling approach allowed us to obtain a molecular electrostatic potential feature which suggests a suitable interaction with the receptor site of the BK channel, from a tri-dimensional point of view. This approach seems to represent a further contribution for the development of new BK-activators, designed on the basis of the pharmacophoric model above-mentioned.