Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Biological Sciences - Article Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic Zuxin Chen, Feng Hong, Jingyi Wang, Dongsheng Chen, Qian Wang, and 30 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5741207/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Yohimbine, a potent alpha2A-adrenergic receptor (α2AAR) antagonist, was found to carry therapeutic potential for type 2 diabetes through improving insulin release. However, adverse side effects mediated by its actions in the brain hampered its use. Here, we have developed a novel peripherally acting α2AAR antagonist, CDS479-2, based on molecular docking analysis and modification of yohimbine's structure. The inactive-state structures of α2AAR, either bound to yohimbine, or bound to CDS479-2, were elucidated via cryo-electron microscopy method. Importantly, CDS479-2 has similar α2AAR antagonist activity as yohimbine, but with very limited access to the brain and thus protecting against the unwanted central effects, such as hypertension and anxiety. Moreover, single dose of CDS479-2 by injection or gavage showed potent glucose-lowering effects in a high-fat diet-induced obesity (DIO) mouse model for human type 2 diabetes. Remarkably, DIO mice having received 2 weeks of daily treatment of CDS479-2, exhibited sustained normoglycaemia, and increased density of insulin-producing beta cells, in which important proliferation related genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to those of healthy control mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. The strategy we employed here may inspire the optimization of other drugs which have both peripheral and central targets. Biological sciences/Chemical biology/Pharmacology/Receptor pharmacology Biological sciences/Physiology/Metabolism/Metabolic diseases/Diabetes/Type 2 diabetes alpha2A-adrenergic receptor (α2AAR) yohimbine T2DM blood-brain barrier (BBB) permeability beta cell regeneration structure modification Cryo-EM Full Text Additional Declarations In this study, animal experiments were approved and overseen by the Institutional Animal Care and Use Committee (IACUC) at the Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (IACUC number: SIAT-IACUC-240425-NS-CZX-A2754). There is NO Competing Interest. Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5741207","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":400106614,"identity":"f704e03a-0e62-4392-a182-2ddd7c11c4db","order_by":0,"name":"Zuxin 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structure modification, Cryo-EM","lastPublishedDoi":"10.21203/rs.3.rs-5741207/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5741207/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Yohimbine, a potent alpha2A-adrenergic receptor (α2AAR) antagonist, was found to carry therapeutic potential for type 2 diabetes through improving insulin release. However, adverse side effects mediated by its actions in the brain hampered its use. Here, we have developed a novel peripherally acting α2AAR antagonist, CDS479-2, based on molecular docking analysis and modification of yohimbine's structure. The inactive-state structures of α2AAR, either bound to yohimbine, or bound to CDS479-2, were elucidated via cryo-electron microscopy method. Importantly, CDS479-2 has similar α2AAR antagonist activity as yohimbine, but with very limited access to the brain and thus protecting against the unwanted central effects, such as hypertension and anxiety. Moreover, single dose of CDS479-2 by injection or gavage showed potent glucose-lowering effects in a high-fat diet-induced obesity (DIO) mouse model for human type 2 diabetes. Remarkably, DIO mice having received 2 weeks of daily treatment of CDS479-2, exhibited sustained normoglycaemia, and increased density of insulin-producing beta cells, in which important proliferation related genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to those of healthy control mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. 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