New dual 5-HT1A and 5-HT7 receptor ligands derived from SYA16263

Eur J Med Chem. 2021 Mar 15:214:113243. doi: 10.1016/j.ejmech.2021.113243. Epub 2021 Feb 3.


We have previously reported that dual 5-HT1A and 5-HT7 receptor ligands might find utility as treatment options for various CNS related conditions including cognitive and anxiolytic impairments. We have also more recently reported that SYA16263 has antipsychotic-like properties with an absence of catalepsy in animal models ascribed to its ability to recruit β-arrestin to the D2 receptor. However, SYA16263 also binds with very high affinity to 5-HT1AR (Ki = 1.1 nM) and a moderate affinity at 5-HT7R (Ki = 90 nM). Thus, it was of interest to exploit its pharmacophore elements in designing new dual receptor ligands. Using SYA16263 as the lead molecule, we have conducted a limited structure-affinity relationship (SAFIR) study by modifying various structural elements in the arylalkyl moiety, resulting in the identification of a new dual 5-HT1AR and 5-HT7R ligand, 6-chloro-2-methyl-2-(3-(4-(pyridin-2-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-inden-1-one (21), which unlike SYA16263, has a sub-nanomolar (5-HT1AR, Ki = 0.74 nM) and a low nanomolar (5-HT7R, Ki = 8.4 nM) affinity for these receptors. Interestingly, 21 is a full agonist at 5-HT1AR and antagonist at the 5-HT7R, functional characteristics which point to its potential as an antidepressant agent.

Keywords: 5-HT subtype Receptors; Dopamine and serotonin receptors; Dual 5-HT(1A) and 5-HT(7) receptors; Indanones; Pyridinyl piperazine; SYA16263.

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Piperazines / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, Serotonin / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Serotonin Antagonists / chemical synthesis
  • Serotonin Antagonists / chemistry
  • Serotonin Antagonists / pharmacology*
  • Structure-Activity Relationship


  • Ligands
  • Piperazines
  • Pyridines
  • Receptors, Serotonin
  • SYA16263
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Antagonists
  • serotonin 7 receptor
  • Receptor, Serotonin, 5-HT1A