Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists

Dehui Zhang, David A. Perrey, Ann M. Decker, Tiffany L. Langston, Vijayakumar Mavanji, Danni L. Harris, Catherine M. Kotz, Yanan Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Loss of orexin-producing neurons results in narcolepsy with cataplexy, and orexin agonists have been shown to increase wakefulness and alleviate narcolepsy symptoms in animal models. Several OX2R agonists have been reported but with little or no activity at OX1R. We conducted structure-activity relationship studies on the OX2R agonist YNT-185 ( 2) and discovered dual agonists such as RTOXA-43 ( 40) with EC 50's of 24 nM at both OX2R and OX1R. Computational modeling studies based on the agonist-bound OX2R cryogenic electron microscopy structures showed that 40 bound in the same binding pocket and interactions of the pyridylmethyl group of 40 with OX1R may have contributed to its high OX1R potency. Intraperitoneal injection of 40 increased time awake, decreased time asleep, and increased sleep/wake consolidation in 12-month old mice. This work provides a promising dual small molecule agonist and supports development of orexin agonists as potential treatments for orexin-deficient disorders such as narcolepsy.

Original languageEnglish (US)
Pages (from-to)8806-8825
Number of pages20
JournalJournal of medicinal chemistry
Volume64
Issue number12
DOIs
StatePublished - Jun 24 2021

Bibliographical note

Funding Information:
This work was supported by the National Institute on Drug Abuse, the National Institutes of Health, U.S. (grants DA040693 to Y.Z.), and the US Department of Veteran Affairs (grants 1IO1BX003004-01A2 and 1IO1BX003687-01A1 to C.M.K.).

Publisher Copyright:
© 2021 American Chemical Society

Keywords

  • Animals
  • CHO Cells
  • Cricetulus
  • Female
  • Male
  • Mice
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Orexin Receptors/agonists
  • Sleep/drug effects
  • Structure-Activity Relationship
  • Sulfonamides/chemical synthesis
  • Wakefulness/drug effects

PubMed: MeSH publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Journal Article
  • Research Support, N.I.H., Extramural

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