{"doi":"10.1021/acsptsci.2c00177","title":"Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice","abstract":"4-Phosphoryloxy-N,N-dimethyltryptamine (psilocybin) is a naturally occurring tertiary amine found in many mushroom species. Psilocybin is a prodrug for 4-hydroxy-N,N-dimethyltryptamine (psilocin), which induces psychedelic effects via agonist activity at the serotonin (5-HT) 2A receptor (5-HT2A). Several other 4-position ring-substituted tryptamines are present in psilocybin-containing mushrooms, including the secondary amine 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin), but these compounds are not well studied. Here, we investigated the structure–activity relationships for psilocybin, baeocystin, and aeruginascin, as compared to their 4-acetoxy and 4-hydroxy analogues, using in vitro and in vivo methods. Broad receptor screening using radioligand binding assays in transfected cells revealed that secondary and tertiary tryptamines with either 4-acetoxy or 4-hydroxy substitutions display nanomolar affinity for most human 5-HT receptor subtypes tested, including the 5-HT2A and the serotonin 1A receptor (5-HT1A). The same compounds displayed affinity for 5-HT2A and 5-HT1A in mouse brain tissue in vitro and exhibited agonist efficacy in assays examining 5-HT2A-mediated calcium mobilization and β-arrestin 2 recruitment. In mouse experiments, only the tertiary amines psilocin, psilocybin, and 4-acetoxy-N,N-dimethyltryptamine (psilacetin) induced head twitch responses (ED50 0.11–0.29 mg/kg) indicative of psychedelic-like activity. Head twitches were blocked by 5-HT2A antagonist pretreatment, supporting 5-HT2A involvement. Both secondary and tertiary amines decreased body temperature and locomotor activity at higher doses, the effects of which were blocked by 5-HT1A antagonist pretreatment. Across all assays, the pharmacological effects of 4-acetoxy and 4-hydroxy compounds were similar, and these compounds were more potent than their 4-phosphoryloxy counterparts. Importantly, psilacetin appears to be a prodrug for psilocin that displays substantial serotonin receptor activities of its own.","journal":"ACS Pharmacology & Translational Science","year":2022,"id":234793,"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":91,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"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":460863,"name":"Eline Pottie","orcid":"0000-0002-9077-4055","position":1,"is_corresponding":false},{"id":405573,"name":"John S. Partilla","orcid":null,"position":2,"is_corresponding":false},{"id":782357,"name":"Alexander M. Sherwood","orcid":"0000-0003-0895-0791","position":3,"is_corresponding":false},{"id":852130,"name":"Kristi W. Kaylo","orcid":null,"position":4,"is_corresponding":false},{"id":851313,"name":"Duyen N. K. Pham","orcid":"0000-0002-8599-1565","position":5,"is_corresponding":false},{"id":852131,"name":"Marilyn Naeem","orcid":null,"position":6,"is_corresponding":false},{"id":414930,"name":"Vamshikrishna Reddy Sammeta","orcid":null,"position":7,"is_corresponding":false},{"id":852132,"name":"Stacie DeBoer","orcid":null,"position":8,"is_corresponding":false},{"id":413848,"name":"James A. Golen","orcid":"0000-0002-6615-1253","position":9,"is_corresponding":false},{"id":519570,"name":"Elliott B. Hulley","orcid":"0000-0002-2630-3689","position":10,"is_corresponding":false},{"id":460864,"name":"Christophe P. Stove","orcid":"0000-0001-7126-348X","position":11,"is_corresponding":false},{"id":851314,"name":"A.R. Chadeayne","orcid":"0000-0003-0449-0337","position":12,"is_corresponding":false},{"id":851315,"name":"David R. Manke","orcid":"0000-0002-2513-4801","position":13,"is_corresponding":false},{"id":289506,"name":"Michael H. Baumann","orcid":"0000-0001-7758-1470","position":14,"is_corresponding":false},{"id":376730,"name":"Grant C. Glatfelter","orcid":"0000-0003-1011-9083","position":0,"is_corresponding":true}],"reference_count":112,"raw_metadata":null,"created_at":"2026-07-19T00:21:42.662304Z","pmid":"36407948","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":[]}