Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia

Eur J Med Chem. 2015 Mar 6:92:221-35. doi: 10.1016/j.ejmech.2014.12.045. Epub 2014 Dec 24.


We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 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 M1 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-indol-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.

Keywords: 5-HT(6)R antagonist; BPSD; D(2)R partial agonist; Dementia; Designed multiple ligand (DML).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Dementia / drug therapy*
  • Dementia / psychology*
  • Dose-Response Relationship, Drug
  • Drug Partial Agonism*
  • Humans
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Ligands
  • Male
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Quinolones / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Serotonin / metabolism*
  • Structure-Activity Relationship
  • Swimming


  • 2-propoxybenzeneamide
  • 4-(piperazin-1-yl)-1H-indole
  • 7-butoxy-3,4-dihydroquinoloin-2(1H)-one
  • Benzamides
  • Indoles
  • Ligands
  • Piperazines
  • Quinolones
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • serotonin 6 receptor