Exploration of synthetic approaches and pharmacological evaluation of PNU-69176E and its stereoisomer as 5-HT2C receptor allosteric modulators

Chunyong Ding, Nicole M. Bremer, Thressa D. Smith, Patricia K. Seitz, Noelle C. Anastasio, Kathryn A. Cunningham, Jia Zhou

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Allosteric modulators of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) present a unique drug design strategy to augment the response to endogenous 5-HT in a site- and event-specific manner with great potential as novel central nervous system probes and therapeutics. To date, PNU-69176E is the only reported selective positive allosteric modulator for the 5-HT2CR. For the first time, an optimized synthetic route to readily access PNU-69176E (1) and its diastereomer 2 has been established in moderate to good overall yields over 10 steps starting from commercially available picolinic acid. This synthetic approach not only enables a feasible preparation of a sufficient amount of 1 for use as a reference compound for secondary pharmacological studies, but also provides an efficient synthesis of key intermediates to develop novel and simplified 5-HT2CR allosteric modulators. Compound 1 and its diastereomer 2 were functionally characterized in Chinese hamster ovary (CHO) cells stably transfected with the 5-HT 2CR using an intracellular calcium (Cai2+) release assay. Compound 1 demonstrated efficacy and potency as an allosteric modulator for the 5-HT2CR with no intrinsic agonist activity. Compound 1 did not alter 5-HT-evoked Cai2+ in CHO cells stably transfected with the highly homologous 5-HT2AR. In contrast, the diastereomer 2 did not alter 5-HT-evoked Cai2+ release in 5-HT2AR-CHO or 5-HT2CR-CHO cells or exhibit intrinsic agonist activity.

Original languageEnglish (US)
Pages (from-to)538-545
Number of pages8
JournalACS chemical neuroscience
Issue number7
StatePublished - Jul 18 2012


  • 5-HT receptor
  • PNU-69176E
  • allosteric modulator
  • diastereomer
  • synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology


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