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Small-Molecule Positive Allosteric Modulators of the β 2 -Adrenoceptor Isolated from DNA-Encoded Libraries.

التفاصيل البيبلوغرافية
العنوان: Small-Molecule Positive Allosteric Modulators of the β 2 -Adrenoceptor Isolated from DNA-Encoded Libraries.
المؤلفون: Ahn S; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Pani B; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Kahsai AW; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Olsen EK; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Husemoen G; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Vestergaard M; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Jin L; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Zhao S; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Wingler LM; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Rambarat PK; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Simhal RK; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Xu TT; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Sun LD; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Shim PJ; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Staus DP; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Huang LY; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Franch T; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Chen X; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.)., Lefkowitz RJ; Departments of Medicine (S.A., B.P., A.W.K., L.M.W., P.K.R., R.K.S., T.T.X., L.D.S., D.P.S., L.-Y.H., R.J.L.) and Biochemistry (R.J.L.) and Howard Hughes Medical Institute (L.M.W., D.P.S., R.J.L.), Duke University Medical Center, Durham, North Carolina; Nuevolution A/S, Copenhagen, Denmark (E.K.O., G.H., M.V., T.F.); Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu, China (L.J., S.Z., X.C.); and Department of Biology, Duke University, Durham, North Carolina (P.J.S.) lefko001@receptor-biol.duke.edu.
المصدر: Molecular pharmacology [Mol Pharmacol] 2018 Aug; Vol. 94 (2), pp. 850-861. Date of Electronic Publication: 2018 May 16.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
مواضيع طبية MeSH: Adrenergic beta-2 Receptor Agonists/*metabolism , Receptors, Adrenergic, beta-2/*chemistry , Receptors, Adrenergic, beta-2/*metabolism , Small Molecule Libraries/*pharmacology, Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Drug Synergism ; GTP-Binding Proteins/metabolism ; Gene Library ; Molecular Structure ; Small Molecule Libraries/chemistry ; Structure-Activity Relationship ; Substrate Specificity ; beta-Arrestin 1/metabolism
مستخلص: Conventional drug discovery efforts at the β 2 -adrenoceptor ( β 2 AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small-molecule libraries, we have discovered and characterized the first β 2 AR small-molecule positive allosteric modulators (PAMs)-compound (Cmpd)-6 [( R )- N -(4-amino-1-(4-( tert -butyl)phenyl)-4-oxobutan-2-yl)-5-( N -isopropyl- N -methylsulfamoyl)-2-((4-methoxyphenyl)thio)benzamide] and its analogs. We used purified human β 2 ARs, occupied by a high-affinity agonist, for the affinity-based screening of over 500 million distinct library compounds, which yielded Cmpd-6. It exhibits a low micro-molar affinity for the agonist-occupied β 2 AR and displays positive cooperativity with orthosteric agonists, thereby enhancing their binding to the receptor and ability to stabilize its active state. Cmpd-6 is cooperative with G protein and β -arrestin1 (a.k.a. arrestin2) to stabilize high-affinity, agonist-bound active states of the β 2 AR and potentiates downstream cAMP production and receptor recruitment of β -arrestin2 (a.k.a. arrestin3). Cmpd-6 is specific for the β 2 AR compared with the closely related β 1 AR. Structure-activity studies of select Cmpd-6 analogs defined the chemical groups that are critical for its biologic activity. We thus introduce the first small-molecule PAMs for the β 2 AR, which may serve as a lead molecule for the development of novel therapeutics. The approach described in this work establishes a broadly applicable proof-of-concept strategy for affinity-based discovery of small-molecule allosteric compounds targeting unique conformational states of GPCRs.
Competing Interests: The authors declare no conflict of interest.
(Copyright © 2018 by The Author(s).)
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معلومات مُعتمدة: R01 HL016037 United States HL NHLBI NIH HHS; T32 HL007101 United States HL NHLBI NIH HHS; United States HHMI Howard Hughes Medical Institute
المشرفين على المادة: 0 (Adrenergic beta-2 Receptor Agonists)
0 (Receptors, Adrenergic, beta-2)
0 (Small Molecule Libraries)
0 (beta-Arrestin 1)
EC 3.6.1.- (GTP-Binding Proteins)
تواريخ الأحداث: Date Created: 20180518 Date Completed: 20190322 Latest Revision: 20190322
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC6022804
DOI: 10.1124/mol.118.111948
PMID: 29769246
قاعدة البيانات: MEDLINE
الوصف
تدمد:1521-0111
DOI:10.1124/mol.118.111948