title: Comparative inhibitory effects of niflumic acid and novel synthetic derivatives on the rat isolated stomach fundus.
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 KCI-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 microM) 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 x 10(4) M (n = 9). In contrast, it was significantly less potent at inhibiting KCl-induced responses (IC50 = 1.49 x 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 x 10(-4) M (n = 8) and 1.87 x 10(-4) M (n = 9) for 5-HT responses, and 2.61 x 10(-4) M (n = 8) and 2.55 x 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.
authors.affiliation: Departamento de Ciências Fisiológicas, CCS, Universidade Estadual do Ceará, Fortaleza, Brazil. criddle@uece.br
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
authors.forename: AnaVanescaP
authors.initials: A
authors.lastname: Meireles
authors.forename: Liana B
authors.initials: LB
authors.lastname: Macêdo
authors.forename: José H
authors.initials: JH
authors.lastname: Leal-Cardoso
authors.forename: Henrique C
authors.initials: HC
authors.lastname: Scarparo
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jaffar
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005748:Gastric Fundus / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009544:Niflumic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D012701:Serotonin; D009544:Niflumic Acid; D011189:Potassium Chloride