Effects of taurine analogues on chloride channel conductance of rat skeletal muscle fibers: a structure-activity relationship investigation

Abstract

In rat skeletal muscle, taurine was proposed to interact with a low affinity binding site on sarcolemmal phospholipids near chloride channel, increasing chloride conductance (GCI). In an attempt to evaluate the structure-activity relationship between taurine and its binding site, a series of N-azacycloalkenyl analogues of taurine (A: N-(1′aza-cyclopenten-2′yl)-2-aminoethane sulfonic acid; B: N-(1′-aza-cyclopenten-2′-yl)-2-aminoethane sulfonic acid; C: N-(1′aza-cyclopenten-2′-yl)-3-amino-propane sulfonic acid; D: N-(1′aza-cyclopenten-2′-yl)-3-aminopropane sulfonic acid) have been synthetized and tested in vitro on rat extensor digitorum longus (EDL) muscle. In spite of the presence of a bulky and lipophilic 5 or 7 membered heterocycle linked to the taurine amino group, analogues A and B determined an increase of GCI, although less potently than taurine. Also 3-aminopropane sulfonic acid (homotaurine), tested in comparison, showed less activity in increasing GCI with respect to taurine, probably for the increased distance between charged groups. Taurine analogues C and D, which differ from compounds A and B for an additional methylene group, showed much lower activity in increasing GCI. It has been reported that guanidinoethane sulfonate (GES) displaces taurine from the low affinity site on sarcolemma by only 7%. This compound, characterized by lower charge density on the guanidinium cationic head, applied in vitro on EDL muscle, show reduced taurine-like activity in increasing GCl. Our results support the hypothesis that the effect of taurine on muscle GCI is due to a specific binding on a low affinity site on sarcolemma and that charge delocalization reduces the binding probability more than the substitution of the primary amino group or the increased distance between charged groups.