B-973, a Novel α7 nAChR Ago-PAM: Racemic and Asymmetric Synthesis, Electrophysiological Studies, and in Vivo Evaluation

  • ACS Med Chem Lett. 2018 Oct 11;9(11):1144-1148. doi: 10.1021/acsmedchemlett.8b00407.
Sumanta Garai  1 ,  Krishnamohan S Raja  1 ,  Roger L Papke  2 ,  Jeffrey R Deschamps  3 ,  M Imad Damaj  4 ,  Ganesh A Thakur  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, Bouvé College of Health Science, Northeastern University, 140 The Fenway, 360 Huntington Avenue, Boston, Massachusetts 02115, United States.
  • 2. Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida 32611, United States.
  • 3. Naval Research Laboratory, Code 6930, 4555 Overlook Avenue, Washington, D.C. 20375, United States.
  • 4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23284, United States.
PMID: 30429960 DOI: 10.1021/acsmedchemlett.8b00407
Abstract

We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray crystallography studies revealed its absolute "S" stereochemistry. B-973B was effective in attenuating pain behavior and decreasing paw edema (formalin test), and its analgesic effects were mediated through α7 nAChR.

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