{"doi":"10.3389/fendo.2021.789957","title":"Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol","abstract":"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 Thr 211 , 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.","journal":"Frontiers in Endocrinology","year":2021,"id":200670,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":778423,"name":"Thomas Coudrat","orcid":"0000-0001-9197-1889","position":1,"is_corresponding":false},{"id":778424,"name":"Aditya J. Desai","orcid":"0000-0002-0075-3470","position":2,"is_corresponding":false},{"id":307910,"name":"Maoqing Dong","orcid":"0000-0002-0775-6762","position":3,"is_corresponding":false},{"id":445378,"name":"Daniela G. Dengler","orcid":"0000-0002-3886-2621","position":4,"is_corresponding":false},{"id":307918,"name":"Sebastian G. B. Furness","orcid":"0000-0001-8655-8221","position":5,"is_corresponding":false},{"id":307919,"name":"Arthur Christopoulos","orcid":"0000-0003-4442-3294","position":6,"is_corresponding":false},{"id":307921,"name":"Denise Wootten","orcid":"0000-0003-4563-1642","position":7,"is_corresponding":false},{"id":393099,"name":"Eduard Sergienko","orcid":"0009-0003-2595-2227","position":8,"is_corresponding":false},{"id":307922,"name":"Patrick M. Sexton","orcid":"0000-0001-8902-2473","position":9,"is_corresponding":false},{"id":307923,"name":"Laurence J. Miller","orcid":"0000-0002-4554-3872","position":10,"is_corresponding":false},{"id":307915,"name":"Kaleeckal G. Harikumar","orcid":"0000-0003-0411-5334","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:50:48.624274Z","pmid":"34950108","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}