Synthesis of new arylpiperazinylalkylthiobenzimidazole, benzothiazole, or benzoxazole derivatives as potent and selective 5-HT1A serotonin receptor ligands.
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.
Siracusa
Maria A
MA
Dipartimento di Scienze Farmaceutiche, Università di Catania, Catania, Italy. siracusa@unict.it
Salerno
Loredana
L
Modica
Maria N
MN
Pittalà
Valeria
V
Romeo
Giuseppe
G
Amato
Maria E
ME
Nowak
Mateusz
M
Bojarski
Andrzej J
AJ
Mereghetti
Ilario
I
Cagnotto
Alfredo
A
Mennini
Tiziana
T
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
D052160:Benzothiazoles; D008024:Ligands; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; D000077489:Piperazine; C005465:benzothiazole