دورية أكاديمية
أعرض في EDS

The development of diphenyleneiodonium analogs as GPR3 agonists.

التفاصيل البيبلوغرافية
العنوان: The development of diphenyleneiodonium analogs as GPR3 agonists.
المؤلفون: Gay EA; Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, USA. Electronic address: egay@rti.org., Harris DL; Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, USA., Wilson JW; Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, USA., Blough BE; Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, USA.
المصدر: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Oct 01; Vol. 94, pp. 129427. Date of Electronic Publication: 2023 Aug 02.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 9107377 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3405 (Electronic) Linking ISSN: 0960894X NLM ISO Abbreviation: Bioorg Med Chem Lett Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science Ltd
Original Publication: Oxford ; New York : Pergamon Press, c1991-
مواضيع طبية MeSH: Receptors, G-Protein-Coupled*/agonists , Drug Inverse Agonism*, Onium Compounds ; Binding Sites
مستخلص: G protein-coupled receptor 3 (GPR3) is an orphan receptor potentially involved in many important physiological processes such as drug abuse, neuropathic pain, and anxiety and depression related disorders. Pharmacological studies of GPR3 have been limited due to the restricted number of known agonists and inverse agonists for this constitutively active receptor. In this medicinal chemistry study, we report the discovery of GPR3 agonists based off the diphenyleneiodonium (DPI) scaffold. The most potent full agonist was the 3-trifluoromethoxy analog (32) with an EC 50 of 260 nM and 90% efficacy compared to DPI. Investigation of a homology model of GPR3 from multiple sequence alignment resulted in the finding of a binding site rich in potential π-π and π-cation interactions stabilizing DPI-scaffold agonists. MMGBSA free energy analysis showed a good correlation with trends in observed EC 50 s. DPI analogs retained the same high receptor selectivity for GPR3 over GPR6 and GPR12 as observed with DPI. Collectively, the DPI analog series shows that order of magnitude improvements in potency with the scaffold were attainable; however, attempts to replace the iodonium ion to make the scaffold more druggable failed.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
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معلومات مُعتمدة: U18 DA052416 United States DA NIDA NIH HHS
فهرسة مساهمة: Keywords: Diphenyleneiodonium; G protein-coupled receptor; GPR3
المشرفين على المادة: 0 (Receptors, G-Protein-Coupled)
6HJ411TU98 (diphenyleneiodonium)
0 (Onium Compounds)
تواريخ الأحداث: Date Created: 20230804 Date Completed: 20230918 Latest Revision: 20231110
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10631289
DOI: 10.1016/j.bmcl.2023.129427
PMID: 37541631
قاعدة البيانات: MEDLINE
الوصف
تدمد:1464-3405
DOI:10.1016/j.bmcl.2023.129427