Comparative inhibitory effects of niflumic acid and novel synthetic derivatives on the rat isolated stomach fundus

Abstract

Abstract Novel derivatives of 2-[3-(trifluoromethyl)-analino]nicotinic acid (niflumic acid) were synthesized. The compounds were compared for their inhibitory effects on 5-hydroxytryptamine (5-HT)- and KCl-induced contraction of the rat fundus. The aim was to assess structure-activity relationships regarding the selectivity and potency of these compounds. Niflumic acid (1–100 μM) concentration-dependently inhibited 5-HT-induced tonic contractions with an IC50 value (concentration reducing the control contractile response by 50%, calculated from semilog graphs) of 0.24 × 10−4 M (n = 9). In contrast, it was significantly less potent at inhibiting KCl-induced responses (IC50 = 1.49 × 10−4 M, n = 9). The methyl ester (NFAme) and amido (NFAm) analogues showed no selectivity between 5-HT- and KCl-induced contractions with IC50 values of 1.64 × 10−4 M (n = 8) and 1.87 × 10−4 M (n = 9) for 5-HT responses, and 2.61 × 10−4 M (n = 8) and 2.55 × 10−4 M (n = 7) for KCl-induced responses, respectively. Our results suggest that alteration of the carboxylic acid moiety of niflumic acid reduces the selectivity and potency of its inhibitory action on 5-HT-induced contractile responses of the rat fundus, possibly via a reduced interaction with calcium-activated chloride channels.