title: Benzimidazole derivatives. Part 5: design and synthesis of new benzimidazole-arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands.
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.
authors.affiliation: Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, E-28040 Madrid, Spain. mluzlr@quim.ucm.es <mluzlr@quim.ucm.es>
authors.forename: María L
authors.initials: ML
authors.lastname: López-Rodríguez
authors.forename: Bellinda
authors.initials: B
authors.lastname: Benhamú
authors.forename: Ma José
authors.initials: MJ
authors.lastname: Morcillo
authors.forename: Ignacio
authors.initials: I
authors.lastname: Tejada
authors.forename: David
authors.initials: D
authors.lastname: Avila
authors.forename: Isabel
authors.initials: I
authors.lastname: Marco
authors.forename: Lucio
authors.initials: L
authors.lastname: Schiapparelli
authors.forename: Diana
authors.initials: D
authors.lastname: Frechilla
authors.forename: Joaquín
authors.initials: J
authors.lastname: Del Río
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D003072:Cognition Disorders / Q000188:drug therapy; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry / Q000378:metabolism; D006168:Guinea Pigs; D006624:Hippocampus / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008024:Ligands; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D058829:Serotonin 5-HT1 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001562:Benzimidazoles; D008024:Ligands; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate)