Synthesis and pharmacological evaluation of aryl/heteroaryl piperazinyl alkyl benzotriazoles as ligands for some serotonin and dopamine receptor subtypes

Abstract

Thirteen [(aryl/heteroaryl-piperazinyl)alkyl]benzotriazoles were prepared as potential trazodone- and buspirone-like drugs. The synthesized compounds displayed from moderate to good affinity to the serotonin 5-HT 1A receptor and only modest or poor affinity to the dopamine D 2 receptor, similar to buspirone. The introduction of substituents on the benzotriazole ring did not improve the affinity to the 5-HT 1A receptor, compared to the previously described unsubstituted derivatives. In a general pharmacological screening, which concerned only three of these compounds so far ( 5, 7 and 13), several in vitro and in vivo activities were observed. The guinea pig ileum contractions, induced either electrically or by several agonists, were strongly inhibited; at higher concentrations also the spontaneous tone of the guinea pig trachea was reduced. Compound 13 exhibited good analgesic activity in mice in the formalin-induced algesia and in the writhing test. The same at 30 mg kg −1 p.o. also displayed antihypertensive activity probably related to calcium channel blockade and adrenergic α 1 antagonism. In binding assays, 13 showed a IC 50=580 nM for displacing [ 3H]prazosin from α 1 receptor. Finally, compound 5 (and, to a minor extent, compound 13) protected mice against potassium cyanide induced hypoxia.