New hybrids of quipazine and trazodone as selective inhibitors of uptake of 5-hydroxytryptamine

Article abstract of DOI:10.1002/jps.2600810120

Two new congeners, 4-(chloropropyl)-1-(2-quinolyl)piperazine- and 2-[3-[4- [2-(quinolyl)]-1-piperazinyl]propyl]-1,2,4-triazolo]4,3-a]pyridin-3(2H)-one, of trazodone were synthesized and found to be potent and selective inhibitors of synaptosomal uptake of 5-hydroxytryptamine [5-HT, serotonin; IC₅₀ = norepinephrine > 5 μM, 5-HT = 210-890 nM], with minimal effects in antagonizing (-)-apomorphine-induced climbing behavior and suppression of spontaneous locomotor activity in mice (ED₅₀ > 50 mg/kg). The two compounds behaved like atypical antidepressants, since they weakly antagonized reserpine-induced hypothermia. The acute toxicity studies have shown that these compounds were less lethal when compared with imipramine or quipazine. Furthermore, chronic treatments (20 mg/kg, daily for 10 and 21 days) significantly decreased the isoprenaline-induced increase in cyclic AMP in the rat brain cortex, suggesting desensitization of β-adrenoceptors. These findings point to the effects of these compounds as potential antidepressants dealing with specific serotonergic mechanisms.