Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol

Kaleeckal G. Harikumar, Thomas Coudrat, Aditya J. Desai, Maoqing Dong, Daniela G. Dengler, Sebastian G.B. Furness, Arthur Christopoulos, Denise Wootten, Eduard A. Sergienko, Patrick M. Sexton, Laurence J. Miller

Research output: Contribution to journalArticlepeer-review


Drugs useful in prevention/treatment of obesity could improve health. Cholecystokinin (CCK) is a key regulator of appetite, working through the type 1 CCK receptor (CCK1R); however, full agonists have not stimulated more weight loss than dieting. We proposed an alternate strategy to target this receptor, while reducing likelihood of side effects and/or toxicity. Positive allosteric modulators (PAMs) with minimal intrinsic agonist activity would enhance CCK action, while maintaining spatial and temporal characteristics of physiologic signaling. This could correct abnormal stimulus–activity coupling observed in a high-cholesterol environment observed in obesity. We utilized high-throughput screening to identify a molecule with this pharmacological profile and studied its basis of action. Compound 1 was a weak partial agonist, with PAM activity to enhance CCK action at CCK1R, but not CCK2R, maintained in both normal and high cholesterol. Compound 1 (10 µM) did not exhibit agonist activity or stimulate internalization of CCK1R. It enhanced CCK activity by slowing the off-rate of bound hormone, increasing its binding affinity. Computational docking of Compound 1 to CCK1R yielded plausible poses. A radioiodinatable photolabile analogue retained Compound 1 pharmacology and covalently labeled CCK1R Thr211, consistent with one proposed pose. Our study identifies a novel, selective, CCK1R PAM that binds to the receptor to enhance action of CCK-8 and CCK-58 in both normal and disease-mimicking high-cholesterol environments. This facilitates the development of compounds that target the physiologic spatial and temporal engagement of CCK1R by CCK that underpins its critical role in metabolic regulation.

Original languageEnglish (US)
Article number789957
JournalFrontiers in Endocrinology
StatePublished - Dec 7 2021


  • allosteric modulation
  • cholecystokinin
  • cholecystokinin receptor
  • cholesterol
  • obesity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism


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