Design, synthesis, and evaluation of substituted alkylindoles that activate G protein-coupled receptors distinct from the cannabinoid CB1 and CB2 receptors
The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence sugg...
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| Vydáno v: | European journal of medicinal chemistry Ročník 249; s. 115123 |
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| Hlavní autoři: | , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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Elsevier Masson SAS
05.03.2023
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| ISSN: | 0223-5234, 1768-3254, 1768-3254 |
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| Abstract | The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [35S]GTPγS and [3H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R. Compounds 10 and 12 stimulated [35S]GTPγS binding (EC50s = 3.5 and 1.1 nM, respectively), and this response was pertussis toxin-sensitive, indicating that AI-sensitive GPCRs couple to Gi/o proteins. Five AI analogues reliably distinguished two binding sites that correspond to the high and low affinity state of AI-sensitive GPCRs coupled or not to G proteins. In silico pharmacophore modeling suggest 3 characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R: 1) an s-cis orientation of the two aromatic rings in AI analogues, 2) a narrow dihedral angle between the carbonyl group and the indole ring plane [i.e., O-C(carbonyl)-C3-C2] and 3) the presence of a carbonyl oxygen. The substituted alkylindoles reported here represent novel chemical tools to study AI-sensitive GPCRs.
[Display omitted]
•Few chemical tools are available to study uncharacterized G protein-coupled receptors activated by the cannabinoid agonist, WIN55212-2.•Development of substituted alkylindoles that activate uncharacterized Gi/o protein-coupled receptors expressed by HEK293 cells.•Pharmacophore modeling suggest chemical characteristics that differentiate uncharacterized G protein-coupled receptors and cannabinoid receptors.•Alkylindole-sensitive receptors expressed by HEK293 cells couple to Gi/o proteins and exhibit a distinct pharmacology than cannabinoid receptors. |
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| AbstractList | The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [35S]GTPγS and [3H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R. Compounds 10 and 12 stimulated [35S]GTPγS binding (EC50s = 3.5 and 1.1 nM, respectively), and this response was pertussis toxin-sensitive, indicating that AI-sensitive GPCRs couple to Gi/o proteins. Five AI analogues reliably distinguished two binding sites that correspond to the high and low affinity state of AI-sensitive GPCRs coupled or not to G proteins. In silico pharmacophore modeling suggest 3 characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R: 1) an s-cis orientation of the two aromatic rings in AI analogues, 2) a narrow dihedral angle between the carbonyl group and the indole ring plane [i.e., O-C(carbonyl)-C3-C2] and 3) the presence of a carbonyl oxygen. The substituted alkylindoles reported here represent novel chemical tools to study AI-sensitive GPCRs.The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [35S]GTPγS and [3H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R. Compounds 10 and 12 stimulated [35S]GTPγS binding (EC50s = 3.5 and 1.1 nM, respectively), and this response was pertussis toxin-sensitive, indicating that AI-sensitive GPCRs couple to Gi/o proteins. Five AI analogues reliably distinguished two binding sites that correspond to the high and low affinity state of AI-sensitive GPCRs coupled or not to G proteins. In silico pharmacophore modeling suggest 3 characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R: 1) an s-cis orientation of the two aromatic rings in AI analogues, 2) a narrow dihedral angle between the carbonyl group and the indole ring plane [i.e., O-C(carbonyl)-C3-C2] and 3) the presence of a carbonyl oxygen. The substituted alkylindoles reported here represent novel chemical tools to study AI-sensitive GPCRs. The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [35S]GTPγS and [3H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R. Compounds 10 and 12 stimulated [35S]GTPγS binding (EC50s = 3.5 and 1.1 nM, respectively), and this response was pertussis toxin-sensitive, indicating that AI-sensitive GPCRs couple to Gi/o proteins. Five AI analogues reliably distinguished two binding sites that correspond to the high and low affinity state of AI-sensitive GPCRs coupled or not to G proteins. In silico pharmacophore modeling suggest 3 characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R: 1) an s-cis orientation of the two aromatic rings in AI analogues, 2) a narrow dihedral angle between the carbonyl group and the indole ring plane [i.e., O-C(carbonyl)-C3-C2] and 3) the presence of a carbonyl oxygen. The substituted alkylindoles reported here represent novel chemical tools to study AI-sensitive GPCRs. [Display omitted] •Few chemical tools are available to study uncharacterized G protein-coupled receptors activated by the cannabinoid agonist, WIN55212-2.•Development of substituted alkylindoles that activate uncharacterized Gi/o protein-coupled receptors expressed by HEK293 cells.•Pharmacophore modeling suggest chemical characteristics that differentiate uncharacterized G protein-coupled receptors and cannabinoid receptors.•Alkylindole-sensitive receptors expressed by HEK293 cells couple to Gi/o proteins and exhibit a distinct pharmacology than cannabinoid receptors. The alkylindole (AI), WIN55212-2, modulates the activity of several proteins, including cannabinoid receptors 1 and 2 (CB1R, CB2R), and at least additional G protein-coupled receptor (GPCR) that remains uncharacterized with respect to its molecular identity and pharmacological profile. Evidence suggests that such AI-sensitive GPCRs are expressed by the human kidney cell line HEK293. We synthesized fourteen novel AI analogues and evaluated their activities at AI-sensitive GPCRs using [35S]GTPγS and [3H]WIN55212-2 binding in HEK293 cell membranes, and performed in silico pharmacophore modeling to identify characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R. Compounds 10 and 12 stimulated [35S]GTPγS binding (EC50s = 3.5 and 1.1 nM, respectively), and this response was pertussis toxin-sensitive, indicating that AI-sensitive GPCRs couple to Gi/o proteins. Five AI analogues reliably distinguished two binding sites that correspond to the high and low affinity state of AI-sensitive GPCRs coupled or not to G proteins. In silico pharmacophore modeling suggest 3 characteristics that favor binding to AI-sensitive GPCRs versus CB1R/CB2R: 1) an s-cis orientation of the two aromatic rings in AI analogues, 2) a narrow dihedral angle between the carbonyl group and the indole ring plane [i.e., O-C(carbonyl)-C3-C2] and 3) the presence of a carbonyl oxygen. The substituted alkylindoles reported here represent novel chemical tools to study AI-sensitive GPCRs. |
| ArticleNumber | 115123 |
| Author | Stella, Nephi Olivas, Kathleen Kreitzer, Faith R. Kline, Toni Huffman, John W. Xu, Cong Hepburn, Seon A. Hurst, Dow P. Wager-Miller, Jim Howlett, Allyn C. Reggio, Patricia Eldeeb, Khalil M. Mackie, Ken |
| AuthorAffiliation | d Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, NC, 27412, USA g Howard L. Hunter Laboratory, Clemson University, Clemson, SC, 29634, USA a Department of Microbiology, University of Washington, Seattle, WA, 98195, USA b Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA e Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Winston-Salem, NC, 27157, USA f Department of Psychological and Brain Sciences and the Gill Center, Indiana University, Bloomington, IN, 47405, USA c Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA |
| AuthorAffiliation_xml | – name: e Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Winston-Salem, NC, 27157, USA – name: b Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA – name: g Howard L. Hunter Laboratory, Clemson University, Clemson, SC, 29634, USA – name: f Department of Psychological and Brain Sciences and the Gill Center, Indiana University, Bloomington, IN, 47405, USA – name: a Department of Microbiology, University of Washington, Seattle, WA, 98195, USA – name: d Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, NC, 27412, USA – name: c Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, 98195, USA |
| Author_xml | – sequence: 1 givenname: Toni surname: Kline fullname: Kline, Toni organization: Department of Microbiology, University of Washington, Seattle, WA, 98195, USA – sequence: 2 givenname: Cong surname: Xu fullname: Xu, Cong organization: Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA – sequence: 3 givenname: Faith R. surname: Kreitzer fullname: Kreitzer, Faith R. organization: Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA – sequence: 4 givenname: Dow P. surname: Hurst fullname: Hurst, Dow P. organization: Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, NC, 27412, USA – sequence: 5 givenname: Khalil M. surname: Eldeeb fullname: Eldeeb, Khalil M. organization: Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Winston-Salem, NC, 27157, USA – sequence: 6 givenname: Jim surname: Wager-Miller fullname: Wager-Miller, Jim organization: Department of Psychological and Brain Sciences and the Gill Center, Indiana University, Bloomington, IN, 47405, USA – sequence: 7 givenname: Kathleen surname: Olivas fullname: Olivas, Kathleen organization: Department of Microbiology, University of Washington, Seattle, WA, 98195, USA – sequence: 8 givenname: Seon A. surname: Hepburn fullname: Hepburn, Seon A. organization: Howard L. Hunter Laboratory, Clemson University, Clemson, SC, 29634, USA – sequence: 9 givenname: John W. surname: Huffman fullname: Huffman, John W. organization: Howard L. Hunter Laboratory, Clemson University, Clemson, SC, 29634, USA – sequence: 10 givenname: Ken surname: Mackie fullname: Mackie, Ken organization: Department of Psychological and Brain Sciences and the Gill Center, Indiana University, Bloomington, IN, 47405, USA – sequence: 11 givenname: Allyn C. surname: Howlett fullname: Howlett, Allyn C. organization: Department of Physiology and Pharmacology, Wake Forest University, School of Medicine, Winston-Salem, NC, 27157, USA – sequence: 12 givenname: Patricia surname: Reggio fullname: Reggio, Patricia organization: Department of Chemistry and Biochemistry, University of North Carolina, Greensboro, NC, 27412, USA – sequence: 13 givenname: Nephi surname: Stella fullname: Stella, Nephi email: nstella@uw.edu organization: Department of Pharmacology, University of Washington, Seattle, WA, 98195, USA |
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| Keywords | Cannabinoids G protein-coupled receptors Alkylindoles |
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