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

Edward Ofori, Edem K. Onyameh, Uma M. Gonela, Chandrashekhar Voshavar, Barbara Bricker, Tracy L. Swanson, Amy J. Eshleman, Jennifer L. Schmachtenberg, Shelley H. Bloom, Aaron J. Janowsky, Seth Y. Ablordeppey

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number113243
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Mar 15 2021


  • 5-HT subtype Receptors
  • Dopamine and serotonin receptors
  • Dual 5-HT and 5-HT receptors
  • Indanones
  • Pyridinyl piperazine
  • SYA16263

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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