ABSTRACT
A series of new mixed benzimidazole-arylpiperazine derivatives were designed by incorporating in general structure III the pharmacophoric elements of 5-HT(1A) and 5-HT(3) receptors. Compounds 1-11 were synthesized and evaluated for binding affinity at both serotoninergic receptors, all of them exhibiting high 5-HT(3)R affinity (K(i)=10-62nM), and derivatives with an o-alkoxy group in the arylpiperazine ring showing nanomolar affinity for the 5-HT(1A)R (K(i)=18-150nM). Additionally, all the synthesized compounds were selective over alpha(1)-adrenergic and dopamine D(2) receptors (K(i)>1000-10,000nM). Compound 3 was selected for further pharmacological characterization due to its interesting binding profile as mixed 5-HT(1A)/5-HT(3) ligand with high affinity for both receptors (5-HT(1A): K(i)=18.0nM, 5-HT(3): K(i)=27.2nM). In vitro and in vivo findings suggest that this compound acts as a partial agonist at 5-HT(1A)Rs and as a 5-HT(3)R antagonist. This novel mixed 5-HT(1A)/5-HT(3) ligand was also effective in preventing the cognitive deficits induced by muscarinic receptor blockade in a passive avoidance learning test, suggesting a potential interest in the treatment of cognitive dysfunction.
Subject(s)
Benzimidazoles/chemical synthesis , Piperazines/chemical synthesis , Serotonin Antagonists/chemical synthesis , Animals , Avoidance Learning/drug effects , Benzimidazoles/pharmacology , Cognition Disorders/drug therapy , Guanosine 5'-O-(3-Thiotriphosphate)/chemistry , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Guinea Pigs , Hippocampus/metabolism , Hypothermia/chemically induced , Ligands , Male , Mice , Muscle Contraction/drug effects , Piperazines/pharmacology , Rats , Rats, Wistar , Serotonin 5-HT1 Receptor Antagonists , Serotonin 5-HT3 Receptor Antagonists , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
Based on a computational model for 5-HT(1A)R-ligand interaction and QSAR studies, we have designed and synthesized a new series of arylpiperazines 2-8 which exhibit high 5-HT(1A)R affinity and selectivity over alpha(1)-adrenergic receptors. Among them, compound CSP-2503 (4) has been pharmacologically characterized as a 5-HT(1A)R agonist at somatodendritic and postsynaptic sites, endowed with anxiolytic properties.