{"doi":"10.1111/bph.15756","title":"A new class of 5‐HT<sub>2A</sub>/5‐HT<sub>2C</sub> receptor inverse agonists: Synthesis, molecular modeling, <i>in vitro</i> and <i>in vivo</i> pharmacology of novel 2‐aminotetralins","abstract":"Background and Purpose The 5‐HT receptor subtypes 5‐HT 2A and 5‐HT 2C are important neurotherapeutic targets, though, obtaining selectivity over 5‐HT 2B and H 1 receptors is challenging. Here, we delineated molecular determinants of selective binding to 5‐HT 2A and 5‐HT 2C receptors for novel 4‐phenyl‐2‐dimethylaminotetralins (4‐PATs). Experimental Approach We synthesized 42 novel 4‐PATs with halogen or aryl moieties at the C(4)‐phenyl meta ‐position. Affinity, function, molecular modeling and 5‐HT 2A receptor mutagenesis studies were performed to understand structure–activity relationships at 5‐HT 2 ‐type and H 1 receptors. Lead 4‐PAT‐type 5‐HT 2A /5‐HT 2C receptor inverse agonists were compared with pimavanserin, a selective 5‐HT 2A /5‐HT 2C receptor inverse agonist approved to treat Parkinson's disease‐related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development. Key Results Most 4‐PAT diastereomers in the (2 S ,4 R )‐configuration bound non‐selectively to 5‐HT 2A , 5‐HT 2C and H 1 receptors, with &gt;100‐fold selectivity over 5‐HT 2B receptors, whereas diastereomers in the (2 R ,4 R )‐configuration bound preferentially to 5‐HT 2A over 5‐HT 2C receptors and had &gt;100‐fold selectivity over 5‐HT 2B and H 1 receptors. Results suggest that G238 5.42 and V235 5.39 in 5‐HT 2A receptors (conserved in 5‐HT 2C receptors) are important for high affinity binding, whereas interactions with T194 5.42 and W158 4.56 determine H 1 receptor affinity. The 4‐PAT analog (2 S ,4 R )‐4‐(4'‐(dimethylamino)‐[1,1'‐biphenyl]‐3‐yl)‐ N , N ‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine, (2 S ,4 R )‐ 2k , a potent and selective 5‐HT 2A /5‐HT 2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity. Conclusions and Implications The novel 4‐PAT chemotype can yield selective 5‐HT 2A /5‐HT 2C receptor inverse agonists for antipsychotic drug development by optimizing ligand–receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H 1 receptors, which may circumvent sedative effects.","journal":"British Journal of Pharmacology","year":2021,"id":194384,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"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":764905,"name":"Munmun Mukherjee","orcid":null,"position":1,"is_corresponding":false},{"id":764205,"name":"Ryan P. McGlynn","orcid":"0000-0001-9293-5441","position":2,"is_corresponding":false},{"id":409994,"name":"Meng Cui","orcid":"0000-0002-3895-135X","position":3,"is_corresponding":false},{"id":428266,"name":"Stephen J. Kohut","orcid":"0000-0002-6906-8818","position":4,"is_corresponding":false},{"id":758433,"name":"Raymond G. Booth","orcid":"0000-0003-2349-6400","position":5,"is_corresponding":false},{"id":764204,"name":"Austen B. Casey","orcid":"0000-0002-4670-851X","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:49:59.476757Z","pmid":"34837227","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":[]}