Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation
| Autor: | Giuliana Ottonello, Sine Mandrup Bertozzi, Francesca Seghetti, Tiziano Bandiera, Andrea Cavalli, Debora Russo, Ilaria Penna, Alessio De Simone, Rita Maria Concetta Di Martino, Giovanni Bottegoni, Andrea Armirotti, Federica Belluti |
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| Přispěvatelé: | Di Martino R.M.C., Bottegoni G., Seghetti F., Russo D., Penna I., De Simone A., Ottonello G., Mandrup Bertozzi S., Armirotti A., Bandiera T., Belluti F., Cavalli A. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Bipolar Disorder
enzymes receptors Pharmacology 01 natural sciences Biochemistry Partial agonist drug discovery Structure-Activity Relationship Pharmacokinetics Dopamine receptor D3 Drug Discovery medicine Humans Bipolar disorder General Pharmacology Toxicology and Pharmaceutics Receptor GSK3B polypharmacology Glycogen Synthase Kinase 3 beta Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Drug discovery Chemistry molecular modeling Organic Chemistry Receptors Dopamine D3 Rational design medicine.disease 0104 chemical sciences enzyme 010404 medicinal & biomolecular chemistry Drug Design Molecular Medicine Antipsychotic Agents |
| Popis: | Due to the complex and multifactorial nature of bipolar disorder (BD), single-target drugs have traditionally provided limited relief with no disease-modifying effects. In line with the polypharmacology paradigm, we attempted to overcome these limitations by devising two series of multitarget-directed ligands endowed with both a partial agonist profile at dopamine receptor D3 (D3R) and inhibitory activity against glycogen synthase kinase 3 beta (GSK-3β). These are two structurally unrelated targets that play independent, yet connected, roles in cognition and mood regulation. Two compounds (7 and 10) emerged as promising D3R/GSK-3β multitarget-directed ligands with nanomolar activity at D3R and low-micromolar inhibition of GSK-3β, thereby confirming, albeit preliminarily, the feasibility of our strategy. Furthermore, 7 showed promising drug-like properties in stability and pharmacokinetic studies. |
| Databáze: | OpenAIRE |
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