Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Maria Elena Meza-Aviña; Mary A. Lingerfelt; Linda M. Console-Bram; Thomas F. Gamage; Haleli Sharir; Kristen E. Gettys; Dow P. Hurst; Evangelia Kotsikorou; Derek M. Shore; Marc G. Caron; Narasinga Rao; Larry S. Barak; Mary E. Abood; Patricia H. Reggio; Mitchell P. Croatt

doi:10.1016/j.bmcl.2016.02.030

Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Maria Elena Meza-Aviña, Mary A. Lingerfelt, Linda M. Console-Bram, Thomas F. Gamage, Haleli Sharir, Kristen E. Gettys, Dow P. Hurst, Evangelia Kotsikorou, Derek M. Shore, Marc G. Caron, Narasinga Rao, Larry S. Barak, Mary E. Abood, Patricia H. Reggio, Mitchell P. Croatt

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure–activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.

Original language	English
Pages (from-to)	1827-1830
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2016.02.030
State	Published - 1 Jan 2016
Externally published	Yes

Keywords

Antagonist
Cancer
GPCR
GPR55
Neuropathic pain

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2016.02.030

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Meza-Aviña, M. E., Lingerfelt, M. A., Console-Bram, L. M., Gamage, T. F., Sharir, H., Gettys, K. E., Hurst, D. P., Kotsikorou, E., Shore, D. M., Caron, M. G., Rao, N., Barak, L. S., Abood, M. E., Reggio, P. H., & Croatt, M. P. (2016). Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones. Bioorganic and Medicinal Chemistry Letters, 26(7), 1827-1830. https://doi.org/10.1016/j.bmcl.2016.02.030

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title = "Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones",

abstract = "A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure–activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.",

keywords = "Antagonist, Cancer, GPCR, GPR55, Neuropathic pain",

author = "Meza-Avi{\~n}a, {Maria Elena} and Lingerfelt, {Mary A.} and Console-Bram, {Linda M.} and Gamage, {Thomas F.} and Haleli Sharir and Gettys, {Kristen E.} and Hurst, {Dow P.} and Evangelia Kotsikorou and Shore, {Derek M.} and Caron, {Marc G.} and Narasinga Rao and Barak, {Larry S.} and Abood, {Mary E.} and Reggio, {Patricia H.} and Croatt, {Mitchell P.}",

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doi = "10.1016/j.bmcl.2016.02.030",

language = "English",

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Meza-Aviña, ME, Lingerfelt, MA, Console-Bram, LM, Gamage, TF, Sharir, H, Gettys, KE, Hurst, DP, Kotsikorou, E, Shore, DM, Caron, MG, Rao, N, Barak, LS, Abood, ME, Reggio, PH & Croatt, MP 2016, 'Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 7, pp. 1827-1830. https://doi.org/10.1016/j.bmcl.2016.02.030

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T1 - Design, synthesis, and analysis of antagonists of GPR55

T2 - Piperidine-substituted 1,3,4-oxadiazol-2-ones

AU - Meza-Aviña, Maria Elena

AU - Lingerfelt, Mary A.

AU - Console-Bram, Linda M.

AU - Gamage, Thomas F.

AU - Sharir, Haleli

AU - Gettys, Kristen E.

AU - Hurst, Dow P.

AU - Kotsikorou, Evangelia

AU - Shore, Derek M.

AU - Caron, Marc G.

AU - Rao, Narasinga

AU - Barak, Larry S.

AU - Abood, Mary E.

AU - Reggio, Patricia H.

AU - Croatt, Mitchell P.

PY - 2016/1/1

Y1 - 2016/1/1

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AB - A series of 1,3,4-oxadiazol-2-ones was synthesized and tested for activity as antagonists at GPR55 in cellular beta-arrestin redistribution assays. The synthesis was designed to be modular in nature so that a sufficient number of analogues could be rapidly accessed to explore initial structure–activity relationships. The design of analogues was guided by the docking of potential compounds into a model of the inactive form of GPR55. The results of the assays were used to learn more about the binding pocket of GPR55. With this oxadiazolone scaffold, it was determined that modification of the aryl group adjacent to the oxadiazolone ring was often detrimental and that the distal cyclopropane was beneficial for activity. These results will guide further exploration of this receptor.

KW - Antagonist

KW - Cancer

KW - GPCR

KW - GPR55

KW - Neuropathic pain

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ER -

Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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