{"doi":"10.3389/fphar.2022.919605","title":"Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593","abstract":"Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R -enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S -enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S -enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo . The R -enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro , and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington’s disease.","journal":"Frontiers in Pharmacology","year":2022,"id":278183,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":314027,"name":"Sumanta Garai","orcid":"0000-0003-4071-8490","position":1,"is_corresponding":false},{"id":950758,"name":"Ayat Zagzoog","orcid":null,"position":2,"is_corresponding":false},{"id":431619,"name":"Dow P. Hurst","orcid":"0000-0002-2382-0031","position":3,"is_corresponding":false},{"id":950759,"name":"Lesley Stevenson","orcid":null,"position":4,"is_corresponding":false},{"id":761204,"name":"Roger G. Pertwee","orcid":"0000-0003-3227-2783","position":5,"is_corresponding":false},{"id":383499,"name":"Gregory H. Imler","orcid":"0000-0002-9686-9186","position":6,"is_corresponding":false},{"id":432929,"name":"Patricia H. Reggio","orcid":null,"position":7,"is_corresponding":false},{"id":402358,"name":"Ganesh A. Thakur","orcid":"0000-0001-8228-5799","position":8,"is_corresponding":false},{"id":690945,"name":"Robert B. Laprairie","orcid":"0000-0002-9994-433X","position":9,"is_corresponding":false},{"id":950757,"name":"Asher L. Brandt","orcid":null,"position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T00:28:43.133347Z","pmid":"36386195","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":[]}