{"doi":"10.1101/2021.04.22.440994","title":"A novel mitragynine analog with low efficacy mu-opioid receptor agonism displays antinociception with attenuated adverse effects","abstract":"ABSTRACT Dried kratom leaves are anecdotally used for the treatment of pain, opioid dependence, and alcohol use disorder. We have previously shown that kratom’s natural products (mitragynine) and semi-synthetic analogs (7-hydroxy mitragynine (7OH) and mitragynine pseudoindoxyl) are mu opioid receptor (MOR) agonists that show minimal β-arrestin2 recruitment. To further investigate the structure activity relationships of G-protein potency, efficacy, and β-arrestin2 recruitment, we diversified the mitragynine/7OH templates at the C9, -10 and -12 positions of the aromatic ring of the indole moiety. Three lead C9 analogs, synthesized by swapping the 9-methoxy group with varied substituents, namely phenyl ( SC11 ), methyl ( SC12 ), 3’-furanyl ( SC13 ), were further characterized using a panel of in vitro and ex vivo electrophysiology assays. All three compounds were partial agonists with lower efficacy than both DAMGO and morphine in heterologous G-protein assays and synaptic physiology. SC11-13 also showed lower recruitment of both β-arrestin subtypes compared to DAMGO, and in assays with limited MOR receptor reserve, the G-protein efficacy of SC11, SC12 and SC13 was comparable to buprenorphine. In mouse models, at equianalgesic doses SC13 showed MOR-dependent analgesia with potency similar to morphine without respiratory depression, hyperlocomotion, constipation, or place conditioning. Taken together, these results suggest that MOR agonists with a G-protein efficacy profile similar to buprenorphine can be developed into opioids that are effective analgesics with greatly reduced liabilities.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":215390,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"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":0.9549,"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":225467,"name":"Jeffrey F. DiBerto","orcid":"0000-0002-8227-2071","position":1,"is_corresponding":false},{"id":647673,"name":"Abdelfattah Faouzi","orcid":"0000-0002-9059-4791","position":2,"is_corresponding":false},{"id":501419,"name":"Sarah M. Bernhard","orcid":"0000-0001-8549-0413","position":3,"is_corresponding":false},{"id":566144,"name":"Anna M. Gutridge","orcid":"0000-0001-6766-6710","position":4,"is_corresponding":false},{"id":328773,"name":"Steven Ramsey","orcid":"0000-0001-7441-3228","position":5,"is_corresponding":false},{"id":477170,"name":"Yuchen Zhou","orcid":"0000-0002-8239-8619","position":6,"is_corresponding":false},{"id":352614,"name":"Davide Provasi","orcid":"0000-0002-2868-303X","position":7,"is_corresponding":false},{"id":647674,"name":"Nitin Nuthikattu","orcid":"0000-0001-5177-9542","position":8,"is_corresponding":false},{"id":647675,"name":"Rahul Jilakara","orcid":"0000-0002-7793-9898","position":9,"is_corresponding":false},{"id":648782,"name":"Melissa Nelson","orcid":null,"position":10,"is_corresponding":false},{"id":310843,"name":"Wesley B. Asher","orcid":"0000-0001-7437-218X","position":11,"is_corresponding":false},{"id":357108,"name":"Shainnel O. Eans","orcid":null,"position":12,"is_corresponding":false},{"id":402499,"name":"Lisa Wilson","orcid":"0000-0001-7770-8726","position":13,"is_corresponding":false},{"id":454834,"name":"Satyanarayana M. Chintala","orcid":"0000-0003-2656-3226","position":14,"is_corresponding":false},{"id":328776,"name":"Marta Filizola","orcid":"0000-0002-4382-8276","position":15,"is_corresponding":false},{"id":452822,"name":"Richard M. van Rijn","orcid":"0000-0002-9957-1633","position":16,"is_corresponding":false},{"id":589306,"name":"Elyssa B. Margolis","orcid":"0000-0001-8777-302X","position":17,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":18,"is_corresponding":false},{"id":355130,"name":"Jay P. McLaughlin","orcid":"0000-0001-9851-9342","position":19,"is_corresponding":false},{"id":225471,"name":"Tao Che","orcid":"0000-0002-1620-3027","position":20,"is_corresponding":false},{"id":647676,"name":"Dalibor Sameš","orcid":"0000-0001-6911-2260","position":21,"is_corresponding":false},{"id":307532,"name":"Jonathan A. Javitch","orcid":"0000-0001-7395-2967","position":22,"is_corresponding":false},{"id":351509,"name":"Susruta Majumdar","orcid":"0000-0002-2931-3823","position":23,"is_corresponding":false},{"id":351508,"name":"Soumen Chakraborty","orcid":"0000-0003-2932-1388","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:52:55.971300Z","pmid":null,"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":[]}