{"doi":"10.3389/fchem.2022.1008233","title":"Discovery of (R)-2-amino-3-triazolpropanoic acid derivatives as NMDA receptor glycine site agonists with GluN2 subunit-specific activity","abstract":"N -Methyl- d -aspartate (NMDA) receptors play critical roles in central nervous system function and are involved in variety of brain disorders. We previously developed a series of ( R )-3-(5-furanyl)carboxamido-2-aminopropanoic acid glycine site agonists with pronounced variation in activity among NMDA receptor GluN1/2A-D subtypes. Here, a series of ( R )-2-amino-3-triazolpropanoic acid analogues with a novel chemical scaffold is designed and their pharmacological properties are evaluated at NMDA receptor subtypes. We found that the triazole can function as a bioisostere for amide to produce glycine site agonists with variation in activity among NMDA receptor subtypes. Compounds 13g and 13i are full and partial agonists, respectively, at GluN1/2C and GluN1/2D with 3- to 7-fold preference in agonist potency for GluN1/2C-D over GluN1/2A-B subtypes. The agonist binding mode of these triazole analogues and the mechanisms by which the triazole ring can serve as a bioisostere for amide were further explored using molecular dynamics simulations. Thus, the novel ( R )-2-amino-3-triazolpropanoic acid derivatives reveal insights to agonist binding at the GluN1 subunit of NMDA receptors and provide new opportunities for the design of glycine site agonists.","journal":"Frontiers in Chemistry","year":2022,"id":284278,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9445,"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":962013,"name":"Georgios Mazis","orcid":null,"position":1,"is_corresponding":false},{"id":339461,"name":"Feng Yi","orcid":"0000-0002-0049-742X","position":2,"is_corresponding":false},{"id":961569,"name":"James S. Lotti","orcid":"0000-0003-4541-1359","position":3,"is_corresponding":false},{"id":962014,"name":"Michael S. Layeux","orcid":null,"position":4,"is_corresponding":false},{"id":568525,"name":"Eric P. Schultz","orcid":"0000-0002-2259-6912","position":5,"is_corresponding":false},{"id":433514,"name":"Lennart Bunch","orcid":"0000-0002-0180-4639","position":6,"is_corresponding":false},{"id":339468,"name":"Kasper B. Hansen","orcid":"0000-0002-3303-4819","position":7,"is_corresponding":false},{"id":512464,"name":"Rasmus P. Clausen","orcid":"0000-0001-9466-9431","position":8,"is_corresponding":false},{"id":512463,"name":"Fabao Zhao","orcid":"0000-0001-7717-0655","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":null,"created_at":"2026-07-19T00:29:32.702533Z","pmid":"36465862","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":[]}