Dual action calcium-sensing receptor modulator unmasks novel mode-switching mechanism

Karen Gregory, Irina Kufareva, Andrew N. Keller, Elham Khajehali, Hee-chang Mun, Mahvash Ayesha Goolam, Rebecca S Mason, Ben Capuano, Arthur Conigrave, Arthur Christopoulos, Katie Leach

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12 Citations (Scopus)


Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.

Original languageEnglish
Pages (from-to)96-109
Number of pages14
JournalACS Pharmacology & Translational Science
Issue number2
Publication statusPublished - 12 Sep 2018


  • allosteric modulator
  • calcium-sensing receptor
  • calhex231

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