{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:31Z","timestamp":1792790371087,"version":"4.5.0"},"posted":{"date-parts":[[2026,10,1]]},"group-title":"Pharmacology and Toxicology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01CA163890"],"award-info":[{"award-number":["R01CA163890"]}]},{"name":"National Institutes of Health","award":["R01CA194496"],"award-info":[{"award-number":["R01CA194496"]}]},{"name":"National Institutes of Health","award":["P30CA118100"],"award-info":[{"award-number":["P30CA118100"]}]},{"name":"Cowboys for Cancer Research Foundation","id":[{"id":"https:\/\/ror.org\/052nngb38","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Center of Biomedical Research Excellence in Authophagy, Inflammation and Metabolism","award":["P20GM121176"],"award-info":[{"award-number":["P20GM121176"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The classical estrogen receptor \u03b1 (ER\u03b1) is a steroid hormone receptor known for its role in both health and disease. ER\u03b1, like its counterpart ER\u03b2, acts as a receptor for its endogenous ligand 17\u03b2-estradiol (E2) and is capable of binding a diverse set of natural and synthetic small molecules. Several screening campaigns have identified various ER ligands, based on the oxabicyclo[3.3.1]-nonene scaffold, that act as ER agonists. One such campaign extensively characterized an oxabicyclic ER agonist, termed AB-1. Herein, we report the synthesis of a series of analogs based on the scaffold of AB-1 (herein termed\n                  <jats:bold>1<\/jats:bold>\n                  ), focusing on the enhancement of their binding to ER\u03b1 and functional potencies in ER-mediated assays. We identify a new substituted compound\n                  <jats:bold>9<\/jats:bold>\n                  that achieves subnanomolar potencies for ER\u03b1 binding (IC\n                  <jats:sub>50<\/jats:sub>\n                  = 0.45 nM) and ER-dependent transcription (EC\n                  <jats:sub>50<\/jats:sub>\n                  = 0.37 nM) and proliferation (EC\n                  <jats:sub>50<\/jats:sub>\n                  = 0.03 nM), with potencies approaching those of\n                  <jats:bold>E2<\/jats:bold>\n                  . The high potency of\n                  <jats:bold>9<\/jats:bold>\n                  provides a promising scaffold for the potential development of new ER\u03b1-targeted therapeutics.\n                <\/jats:p>","DOI":"10.64898\/2026.09.25.754525","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T02:30:20Z","timestamp":1790908220000},"source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ER\u03b1"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9288-897X","authenticated-orcid":false,"given":"Richard A.","family":"Pepermans","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio J.","family":"Tenorio","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Travis","family":"Saxon","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7559-9666","authenticated-orcid":false,"given":"Marat R.","family":"Talipov","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-2273","authenticated-orcid":false,"given":"William A.","family":"Maio","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chinnasamy","family":"Ramesh","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9190-8302","authenticated-orcid":false,"given":"Eric R.","family":"Prossnitz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Molecular Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA"},{"name":"Center of Biomedical Research Excellence in Autophagy, Inflammation and Metabolism University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA"},{"name":"University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico 87131, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9133-2892","authenticated-orcid":false,"given":"Jeffrey B.","family":"Arterburn","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico, 88003, USA"},{"name":"University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico 87131, 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