title: Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands.
abstract: A series of new compounds containing a benzimidazole, benzothiazole, or benzoxazole nucleus linked to an arylpiperazine by different thioalkyl chains was prepared. They were tested in radioligand binding experiments to evaluate their affinity for 5-HT 1A and 5-HT 2A serotonergic, alpha 1 adrenergic, D1, and D2 dopaminergic receptors. Many of tested compounds showed an interesting binding profile; in particular, 36 displayed very high 5-HT 1A receptor affinity and selectivity over all the other investigated receptors. Selected compounds, evaluated in functional assays, showed antagonistic or partial agonistic activity at 5-HT 1A receptor. An extensive conformational research using both NMR and modeling techniques indicated that extended conformations predominated in vacuum, in solution and during interactions with 5-HT 1A receptor. Finally, the elaborated binding mode of selected compounds at 5-HT 1A receptor was used to explain the influence of spacer length on ligands affinity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Catania, Catania, Italy. siracusa@unict.it
authors.forename: Maria A
authors.initials: MA
authors.lastname: Siracusa
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.forename: Maria N
authors.initials: MN
authors.lastname: Modica
authors.forename: Valeria
authors.initials: V
authors.lastname: Pittalà
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.forename: Maria E
authors.initials: ME
authors.lastname: Amato
authors.forename: Mateusz
authors.initials: M
authors.lastname: Nowak
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Bojarski
authors.forename: Ilario
authors.initials: I
authors.lastname: Mereghetti
authors.forename: Alfredo
authors.initials: A
authors.lastname: Cagnotto
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
mesh_terms: D000478:Alkylation; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D058829:Serotonin 5-HT1 Receptor Antagonists; D013329:Structure-Activity Relationship
chemical_list: D052160:Benzothiazoles; D008024:Ligands; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D000077489:Piperazine; C005465:benzothiazole