{"doi":"10.1073/pnas.2112397119","title":"Discovery of a functionally selective ghrelin receptor (GHSR <sub>1a</sub> ) ligand for modulating brain dopamine","abstract":"Significance The modulation of growth hormone secretagogue receptor-1a (GHSR 1a ) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR 1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein– and β-arrestin (βarr)–dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR 1a conformations toward Gα q activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR 1a -related brain disorders involving the pathological dysregulation of dopamine.","journal":"Proceedings of the National Academy of Sciences","year":2022,"id":257277,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":26236,"name":"D. W. Kim","orcid":"0000-0002-9635-1491","position":1,"is_corresponding":false},{"id":725351,"name":"Yang Zhou","orcid":"0000-0001-5199-156X","position":2,"is_corresponding":false},{"id":708388,"name":"Daniel J. Jansen","orcid":null,"position":3,"is_corresponding":false},{"id":258558,"name":"Lauren M. Slosky","orcid":"0000-0002-9471-9117","position":4,"is_corresponding":false},{"id":573093,"name":"Nicholas Clark","orcid":null,"position":5,"is_corresponding":false},{"id":261060,"name":"Caroline Ray","orcid":null,"position":6,"is_corresponding":false},{"id":267852,"name":"Xin Hu","orcid":"0000-0003-1164-5130","position":7,"is_corresponding":false},{"id":95324,"name":"Noel Southall","orcid":"0000-0003-4500-880X","position":8,"is_corresponding":false},{"id":907210,"name":"Anyang Wang","orcid":"0000-0002-5031-4660","position":9,"is_corresponding":false},{"id":239790,"name":"Xin Xu","orcid":"0000-0003-1163-9304","position":10,"is_corresponding":false},{"id":354890,"name":"Elena Barnaeva","orcid":null,"position":11,"is_corresponding":false},{"id":258568,"name":"William C. Wetsel","orcid":"0000-0002-3592-7397","position":12,"is_corresponding":false},{"id":228425,"name":"Marc Ferrer","orcid":"0000-0003-4569-9137","position":13,"is_corresponding":false},{"id":228431,"name":"Juan Marugán","orcid":"0000-0002-3951-7061","position":14,"is_corresponding":false},{"id":258571,"name":"Marc G. Caron","orcid":"0000-0003-0172-2710","position":15,"is_corresponding":false},{"id":258570,"name":"Lawrence S Barak","orcid":"0000-0002-9170-2141","position":16,"is_corresponding":false},{"id":258560,"name":"Krisztián Tóth","orcid":"0000-0002-6590-6394","position":17,"is_corresponding":false},{"id":572385,"name":"Joshua D. Gross","orcid":"0000-0002-0925-6331","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T00:25:30.183987Z","pmid":"35239443","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":[]}