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Molecular Pharmacology

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Research ArticleArticle

Pharmacological Analysis and Structure Determination of 7-Methylcyanopindolol–Bound β1-Adrenergic Receptor

Tomomi Sato, Jillian Baker, Tony Warne, Giles A. Brown, Andrew G.W. Leslie, Miles Congreve and Christopher G. Tate
Molecular Pharmacology December 2015, 88 (6) 1024-1034; DOI: https://doi.org/10.1124/mol.115.101030
Tomomi Sato
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Jillian Baker
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Tony Warne
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Giles A. Brown
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Andrew G.W. Leslie
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Miles Congreve
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Christopher G. Tate
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom (T.S., T.W., A.G.W.L., C.G.T.); Heptares Therapeutics Ltd, Welwyn Garden City, United Kingdom (G.A.B., M.C.); School of Life Sciences, University of Nottingham, Medical School, Queen’s Medical Centre, Nottingham, United Kingdom (J.B.); KEK High Energy Accelerator Research Organization, Institute of Materials Structure Science, Structural Biology Research Center, Tsukuba, Japan (T.S.)
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Abstract

Comparisons between structures of the β1-adrenergic receptor (AR) bound to either agonists, partial agonists, or weak partial agonists led to the proposal that rotamer changes of Ser5.46, coupled to a contraction of the binding pocket, are sufficient to increase the probability of receptor activation. (RS)-4-[3-(tert-butylamino)-2-hydroxypropoxy]-1H-indole-2-carbonitrile (cyanopindolol) is a weak partial agonist of β1AR and, based on the hypothesis above, we predicted that the addition of a methyl group to form 4-[(2S)-3-(tert-butylamino)-2-hydroxypropoxy]-7-methyl-1H-indole-2-carbonitrile (7-methylcyanopindolol) would dramatically reduce its efficacy. An eight-step synthesis of 7-methylcyanopindolol was developed and its pharmacology was analyzed. 7-Methylcyanopindolol bound with similar affinity to cyanopindolol to both β1AR and β2AR. As predicted, the efficacy of 7-methylcyanopindolol was reduced significantly compared with cyanopindolol, acting as a very weak partial agonist of turkey β1AR and an inverse agonist of human β2AR. The structure of 7-methylcyanopindolol–bound β1AR was determined to 2.4-Å resolution and found to be virtually identical to the structure of cyanopindolol-bound β1AR. The major differences in the orthosteric binding pocket are that it has expanded by 0.3 Å in 7-methylcyanopindolol–bound β1AR and the hydroxyl group of Ser5.46 is positioned 0.8 Å further from the ligand, with respect to the position of the Ser5.46 side chain in cyanopindolol-bound β1AR. Thus, the molecular basis for the reduction in efficacy of 7-methylcyanopindolol compared with cyanopindolol may be regarded as the opposite of the mechanism proposed for the increase in efficacy of agonists compared with antagonists.

Footnotes

    • Received July 27, 2015.
    • Accepted September 17, 2015.
  • C.G.T. is a consultant for Heptares Therapeutics Ltd. This work was funded by a core grant from the Medical Research Council to C.G.T. [Grant MRC U105197215] and A.G.W.L. [Grant MRC U105184325] and a Wellcome Trust Clinician Scientist Fellowship awarded to J.G.B. [Grant number 073377/Z/03/Z].

  • dx.doi.org/10.1124/mol.115.101030.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (6)
Molecular Pharmacology
Vol. 88, Issue 6
1 Dec 2015
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Research ArticleArticle

Structure of 7-Methylcyanopindolol–Bound β1AR

Tomomi Sato, Jillian Baker, Tony Warne, Giles A. Brown, Andrew G.W. Leslie, Miles Congreve and Christopher G. Tate
Molecular Pharmacology December 1, 2015, 88 (6) 1024-1034; DOI: https://doi.org/10.1124/mol.115.101030

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Research ArticleArticle

Structure of 7-Methylcyanopindolol–Bound β1AR

Tomomi Sato, Jillian Baker, Tony Warne, Giles A. Brown, Andrew G.W. Leslie, Miles Congreve and Christopher G. Tate
Molecular Pharmacology December 1, 2015, 88 (6) 1024-1034; DOI: https://doi.org/10.1124/mol.115.101030
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