Pharmacological screening of some quinoline derivatives in canine vascular smooth muscle

ABSTRACT

In order to develop drugs wich can discriminate vascular 5-HT1-like receptos, this study aalyzed the agonist/antagonist interactions of several quinoline derivatives in vascular tissues containing these receptors. 5/HT and several substituted quinolines were evaluated and compared in canine basilar artery rings and saphenous vein helical strips wich were mounted in organ baths for monitoring isometric tension changes. Based upon the molecular features of quipazine, the main assayed variations included some substitutions at the 4-position of piperazine and miscellaneous substitutions at the 2-position of the quinoline nucleus. The rsults, in terms of agonist-induced contraction and-or antagonism of 5-HT-induced contraction revealed that a) 4-alylation of the piperazinyl mioety moderately increases the agonist efficacy; b) halogenation or methylation at 5-or 6-position of both 1-piperazinyl-and 4-methyl-1-piperazinyl quinolines completely abolishes agonist activity; c) introduction of larger substituents (i.e., alkyl, carbethoxy, acethoxyalkyl, aromatic and non/aromatic rings) at the 4-position of the piperazinyl moiety, notably decreases or even abolishes the agonist activity; d) replacement of the piperainyl group by an aminoethyl moiety impotantly increases potency (more than threefold) and efficacy (more than twofold). These findings represent leads which may aid the subsequent desing of vascular 5-HT1-like-selective agents