ABSTRACT
The positive inotropic effect of a series of 4-amino-7-methyl-1,8-naphthyridine-3-carboxylic acid derivatives was compared with the effects of known inotropic agents (ouabain, dihydroouabain, isoproterenol, adrenaline, histamine and isobutylmethylxanthine) in guinea-pig atrial and ventricular myocardial preparations. With respect to their functional effects, the 1,8-naphthyridine compounds are clearly different from drugs acting on the cAMP system, whereas several similarities with cardiac glycoside effects were found. Their ability to inhibit [3H]ouabain binding in guinea-pig cardiac membranes correlates well with their effects on myocardial contractile force. However, the latter effect was exerted by tenfold lower concentrations. The dissimilarities found between the 1,8-naphthyridines and digitalis may be due to a different type of interaction with the binding site on the (Na(+) + K+)-ATPase.
Subject(s)
Carboxylic Acids/pharmacokinetics , Cardiotonic Agents/pharmacokinetics , Animals , Guinea Pigs , In Vitro Techniques , Membranes/metabolism , Myocardial Contraction/drug effects , Myocardium/metabolism , Ouabain/pharmacokinetics , Radioligand Assay , SwineABSTRACT
In order to gain insight into structure-activity relationships concerning the positive inotropic effect of N-heterocycles, a series of 1,8-naphthyridines was synthesized by two different methods. First, 4-hydroxy substituted derivatives were accessible by cyclization of 2-vinylamino-1,8-naphthyridines using diphenyl-ether followed by chlorination and nucleophilic reactions with various amino compounds. Second, 2-amino-nicotinic acid was transformed to 2-alkylamino-1,8-naphthyridines involving a variation of the Friedländer synthesis as well as many subsequent steps. The effect of the compounds on myocardial contractility was assessed in guinea pig left atria paced at 3 Hz. In general, the concentrations for positive inotropism ranged in between 10(-6)-10(-4) mol/l. The compounds differed considerably with respect to the efficacy of the increase in contractile force. The pharmacological investigations appear to demonstrate the following requirements for the pharmacophoric structure. In connection with a lipophilic ester function in 3-position the target compounds have to contain an alkylamino side chain at C-4 bearing a pi-electron-rich center in a definite distance to the NH-function.