title: New hybrids of quipazine and trazodone as selective inhibitors of uptake of 5-hydroxytryptamine.
abstract: 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 greater than 5 microM, 5-HT = 210-890 nM], with minimal effects in antagonizing (-)-apomorphine-induced climbing behavior and suppression of spontaneous locomotor activity in mice (ED50 greater than 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 beta-adrenoceptors. These findings point to the effects of these compounds as potential antidepressants dealing with specific serotonergic mechanisms.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: A A
authors.initials: AA
authors.lastname: Alhaider
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D007099:Imipramine / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011814:Quipazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D014196:Trazodone / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D010879:Piperazines; D011728:Pyridones; D011804:Quinolines; D011943:Receptors, Adrenergic, beta; C075475:4-(chloropropyl)-1-(2-quinolyl)piperazine; C075476:2-(3-(4-(2-quinolyl))-1-piperazinyl)propyl-1,2,4-triazolo(4,3-a)pyridin-3(2H)-one; D012701:Serotonin; D011814:Quipazine; D000242:Cyclic AMP; D007545:Isoproterenol; D007099:Imipramine; D009638:Norepinephrine; D014196:Trazodone