{"doi":"10.1021/jacs.4c03092","title":"Elucidating and Optimizing the Photochemical Mechanism of Coumarin-Caged Tertiary Amines","abstract":"High Resolution Image Download MS PowerPoint Slide Photoactivatable or “caged” pharmacological agents combine the high spatiotemporal specificity of light application with the molecular specificity of drugs. A key factor in all optopharmacology experiments is the mechanism of uncaging, which dictates the photochemical quantum yield and determines the byproducts produced by the light-driven chemical reaction. In previous work, we demonstrated that coumarin-based photolabile groups could be used to cage tertiary amine drugs as quaternary ammonium salts. Although stable, water-soluble, and useful for experiments in brain tissue, these first-generation compounds exhibit relatively low uncaging quantum yield (Φ u < 1%) and release the toxic byproduct formaldehyde upon photolysis. Here, we elucidate the photochemical mechanisms of coumarin-caged tertiary amines and then optimize the major pathway using chemical modification. We discovered that the combination of 3,3-dicarboxyazetidine and bromine substituents shift the mechanism of release to heterolysis, eliminating the formaldehyde byproduct and giving photolabile tertiary amine drugs with Φ u > 20%─a 35-fold increase in uncaging efficiency. This new “ABC” cage allows synthesis of improved photoactivatable derivatives of escitalopram and nicotine along with a novel caged agonist of the oxytocin receptor.","journal":"Journal of the American Chemical Society","year":2024,"id":456204,"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":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1281087,"name":"Xiao-Tao Jin","orcid":null,"position":1,"is_corresponding":false},{"id":581325,"name":"Tanya L. Dilan","orcid":"0000-0002-3944-8385","position":2,"is_corresponding":false},{"id":255527,"name":"Shu‐Hsien Sheu","orcid":"0000-0003-0758-4654","position":3,"is_corresponding":false},{"id":561029,"name":"David E. Clapham","orcid":"0000-0002-4459-9428","position":4,"is_corresponding":false},{"id":944016,"name":"Ryan M. Drenan","orcid":"0000-0002-8141-8577","position":5,"is_corresponding":false},{"id":249822,"name":"Luke D. Lavis","orcid":"0000-0002-0789-6343","position":6,"is_corresponding":false},{"id":249813,"name":"Sambashiva Banala","orcid":"0000-0002-9463-7664","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:03:27.785212Z","pmid":"39023430","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":[]}