Journal of JPP 2002, 54: 283–288 # 2002 The Authors Received May 18, 2001 Accepted September 21, 2001 ISSN 0022-3573 Comparative inhibitory effects of niumic acid and novel synthetic derivatives on the rat isolated stomach fundus David N. Criddle, Ana Vanesca P. Meireles, Liana B. Mace # do, Jose ´ H. Leal-Cardoso, Henrique C. Scarparo and Mohammed Jaffar Abstract Novel derivatives of 2-[3-(triuoromethyl)-analino]nicotinic acid (niumic acid) were syn- thesized. 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. Niumic acid (1–100 lM) concentration-dependently inhibited 5-HT-induced tonic contractions with an IC50 value (concentration reducing the control contractile response by 50%, calculated from semi- log graphs) of 0.24¬10 - 4 M (n ¯ 9). In contrast, it was signicantly 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 niumic 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. Introduction The putative excitatory role of calcium-activated chloride (Cl (Ca) ) channels in the contractile action of various neurotransmitters on vascular and non-vascular smooth muscle has received growing interest (Large & Wang 1996; Chipper®eld & Harper 2000). This has largely been due to the development of relatively selective inhibitors of these channels, such as the fenamates, typi®ed by ni¯umic acid. This compound has been shown to inhibit calcium-activated chloride currents (I Cl(Ca) ) in isolated smooth muscle cells (Pacaud et al 1989; Akbarali & Giles 1993; Hogg et al 1994; Lamb et al 1994), although the exact mechanism of interaction of ni¯umic acid with the ion channel remains unclear. Nevertheless, ni¯umic acid has been increasingly utilized as a pharmacological tool for investigation of Cl (Ca) channels in functional studies in isolated tissues. We have previously demonstrated that ni¯umic acid inhibits noradrenaline (norepinephrine)-induced contraction of isolated rat aorta and, on the basis of comparative data with nifedipine, suggested that activation of Cl (Ca) channels may lead to a depolarization-induced opening of voltage-dependent calcium channels (VDCCs) causing extracellular calcium entry and consequent contraction (Criddle et al 1996). Subsequent studies have provided supportive data for this hypothesis in a number of smooth muscle preparations Laborato ´ rio de Farmacologia dos Canais Io ˆ nicos, Departamento de Cie ˆ ncias Fisiolo ´ gicas, CCS, Universidade Estadual do Ceara ´, Av. Paranjana 1700, Fortaleza CE 60740-000, Brazil David N. Criddle, Ana Vanesca P. Meireles, Liana B. Mace ˆ do, Jose ´ H. Leal-Cardoso Departamento de Farmacologia e Fisiologia, Faculdade de Medicina, Universidade Federal do Ceara ´ , Cel. Nunes de Melo 1127, Porangabussu, Fortaleza, CE, Brazil Henrique C. Scarparo Department of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, M13 9PL, UK Mohammed Jaffar Correspondence : D. N. Criddle, Departamento de Cie ˆ ncias Fisiolo ´ gicas, CCS, Universidade Estadual do Ceara ´, Av. Paranjana 1700, Fortaleza CE 60740-000, Brazil. E-mail : criddle!uece.br Funding : This study was supported by the CNPq and FUNCAP. 283