title: Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and alpha1 receptor binding affinity.
abstract: A series of triazolopyridine derivatives (compounds 2a-l) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT2A and alpha1 receptors. All of the synthesized compounds show a decrease of affinity for both 5HT2A and alpha1 receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an alpha position to the aliphatic nitrogen atom N1. These compounds showed a decrease of affinity only for the alpha1 receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)-2c showed the most significant differences between 5HT2A and alpha1 receptor affinity (IC50 values) and among the corresponding functional properties (pA2 values). Since (S)-2c cannot generate the metabolite 4-(3-chlorophenyl)piperazine this product was selected for further pharmacological studies.
authors.affiliation: Departments of Medicinal Chemistry and Neuropharmacology, Angelini Ricerche S.p.A., P.le della Stazione, 00040 S. Palomba-Pomezia (Rm), Italy.
authors.forename: M
authors.initials: M
authors.lastname: Giannangeli
authors.forename: N
authors.initials: N
authors.lastname: Cazzolla
authors.forename: M R
authors.initials: MR
authors.lastname: Luparini
authors.forename: M
authors.initials: M
authors.lastname: Magnani
authors.forename: M
authors.initials: M
authors.lastname: Mabilia
authors.forename: G
authors.initials: G
authors.lastname: Picconi
authors.forename: M
authors.initials: M
authors.lastname: Tomaselli
authors.forename: L
authors.initials: L
authors.lastname: Baiocchi
mesh_terms: D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry; D044402:Receptor, Serotonin, 5-HT2A; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014196:Trazodone / Q000737:chemistry* / Q000378:metabolism*