Benzimidazole derivatives. Part 5: Design and synthesis of new benzimidazole–arylpiperazine derivatives acting as mixed 5-HT1A/5-HT3 ligands
| Autor: | Bellinda Benhamú, Isabel Marco, Lucio Schiapparelli, Joaquín Del Río, Ignacio Tejada, David Ávila, M. J. Morcillo, María L. López-Rodríguez, Diana Frechilla |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Benzimidazole Stereochemistry medicine.drug_class Guinea Pigs Clinical Biochemistry Pharmaceutical Science Carboxamide Hypothermia Serotonin 5-HT1 Receptor Antagonists Ligands Hippocampus Biochemistry Partial agonist Chemical synthesis Piperazines Mice Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Avoidance Learning medicine Animals Serotonin 5-HT3 Receptor Antagonists Rats Wistar Receptor Molecular Biology 5-HT receptor Bicyclic molecule Organic Chemistry Ligand (biochemistry) Rats chemistry Guanosine 5'-O-(3-Thiotriphosphate) Molecular Medicine Benzimidazoles Serotonin Antagonists Cognition Disorders Muscle Contraction |
| Zdroj: | Bioorganic & Medicinal Chemistry. 12:5181-5191 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2004.07.023 |
| Popis: | 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 = 10–62 nM), and derivatives with an o -alkoxy group in the arylpiperazine ring showing nanomolar affinity for the 5-HT 1A R ( K i = 18–150 nM). Additionally, all the synthesized compounds were selective over α 1 -adrenergic and dopamine D 2 receptors ( K i >1000–10,000 nM). 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 = 18.0 nM, 5-HT 3 : K i = 27.2 nM). 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. |
| Databáze: | OpenAIRE |
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