Pharmacological screening of some quinoline derivatives in canine vascular smooth muscle

In order to develop drugs which can discriminate vascular 5-HT1-like receptors, this study analyzed 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 which 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 results, in terms of agonist-induced contraction and/or antagonism of 5-HT-induced contraction revealed that: a) 4-alkylation of the piperazinyl moiety 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 piperazinyl group by an amino-ethyl moiety importantly increases potency (more than threefold) and efficacy (more than twofold). These findings represent leads which may aid the subsequent design of vascular 5-HT1-like-selective agents.