Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation

Rita Maria Concetta Di Martino, Giovanni Bottegoni, Francesca Seghetti, Debora Russo, Ilaria Penna, Alessio De Simone, Giuliana Ottonello, Sine Mandrup Bertozzi, Andrea Armirotti, Tiziano Bandiera, Federica Belluti, Andrea Cavalli

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

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.

Lingua originaleInglese
pagine (da-a)949-954
Numero di pagine6
RivistaChemMedChem
Volume15
Numero di pubblicazione11
DOI
Stato di pubblicazionePubblicato - 4 giu 2020
Pubblicato esternamente

Fingerprint

Entra nei temi di ricerca di 'Multitarget Compounds for Bipolar Disorder: From Rational Design to Preliminary Pharmacokinetic Evaluation'. Insieme formano una fingerprint unica.

Cita questo