Novel 5-HT6 receptor antagonists/D-2 receptor partial agonists targeting behavioral and psychological symptoms of dementia

作者：Kolaczkowski Marcin^*; Marcinkowska Monika; Bucki Adam; Sniecikowska Joanna; Pawlowski Maciej; Kazek Grzegorz; Siwek Agata; Jastrzeska Wivsek Magdalena; Partyka Anna; Wasik Anna; Wesolowska Anna; Mierzejewski Pawel; Bienkowski Przemyslaw

来源：European Journal of Medicinal Chemistry, 2015, 92: 221-235.

DOI：10.1016/j.ejmech.2014.12.045

• Designed multiple ligand (DML)
• D2R partial agonist
• 5-HT6R antagonist
• Dementia
• BPSD

We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D-2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M-1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indo1-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.

• 出版日期2015-3-6