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Science 23 October 1998:
Vol. 282. no. 5389, pp. 737 - 740
DOI: 10.1126/science.282.5389.737
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Reports

Rapid Identification of Subtype-Selective Agonists of the Somatostatin Receptor Through Combinatorial Chemistry

Susan P. Rohrer, * Elizabeth T. Birzin, Ralph T. Mosley, Scott C. Berk, Steven M. Hutchins, Dong-Ming Shen, Yusheng Xiong, Edward C. Hayes, Rupa M. Parmar, Forrest Foor, Sudha W. Mitra, Sylvia J. Degrado, Min Shu, John M. Klopp, Sheng-Jian Cai, Allan Blake, Wanda W. S. Chan, Alex Pasternak, Lihu Yang, Arthur A. Patchett, Roy G. Smith, Kevin T. Chapman, James M. Schaeffer

Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.

S. P. Rohrer, E. T. Birzin, E. C. Hayes, R. M. Parmar, F. Foor, S. W. Mitra, S.-J. Cai, A. Blake, W. W. S. Chan, R. G. Smith, J. M. Schaeffer, Department of Cell Biochemistry and Physiology, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA. R. T. Mosley, S. C. Berk, S. M. Hutchins, D.-M. Shen, Y. Xiong, S. J. Degrado, M. Shu, J. M. Klopp, K. T. Chapman, Department of Molecular Design and Diversity, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA. A. Pasternak, L. Yang, A. A. Patchett, Department of Medicinal Chemistry, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA.
*   To whom correspondence should be addressed. E-mail: susan_rohrer{at}merck.com

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J. C. Reubi, J.-C. Schaer, S. Wenger, C. Hoeger, J. Erchegyi, B. Waser, and J. Rivier (2000)
PNAS
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Modulation of Pituitary Somatostatin Receptor Subtype (sst1-5) Messenger Ribonucleic Acid Levels by Changes in the Growth Hormone Axis.
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V. Martínez, J. Rivier, D. Coy, and Y. Taché (2000)
J. Pharmacol. Exp. Ther. 293, 1099-1105
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Somatostatin Inhibits Follicle-Stimulating Hormone-Induced Adenylyl Cyclase Activity and Proliferation in Immature Porcine Sertoli Cell via sst2 Receptor.
S. Krantic and M. Benahmed (2000)
Biol Reprod 62, 1835-1843
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Distribution, Targeting, and Internalization of the sst4 Somatostatin Receptor in Rat Brain.
M. Schreff, S. Schulz, M. Handel, G. Keilhoff, H. Braun, G. Pereira, M. Klutzny, H. Schmidt, G. Wolf, and V. Hollt (2000)
J. Neurosci. 20, 3785-3797
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Clin. Cancer Res. 6, 1865-1874
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PNAS 97, 2419-2424
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Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors.
U. Gether (2000)
Endocr. Rev. 21, 90-113
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Somatostatin Inhibits Insulin and Glucagon Secretion via Two Receptor Subtypes: An in Vitro Study of Pancreatic Islets from Somatostatin Receptor 2 Knockout Mice.
M. Z. Strowski, R. M. Parmar, A. D. Blake, and J. M. Schaeffer (2000)
Endocrinology 141, 111-117
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Cloning of the Mouse Somatostatin Receptor Subtype 5 Gene: Promoter Structure and Function.
D. F. Gordon, W. W. Woodmansee, S. R. Lewis, R. A. James, W. M. Wood, and E. C. Ridgway (1999)
Endocrinology 140, 5598-5608
   Abstract »    Full Text »
Quantitative and Functional Expression of Somatostatin Receptor Subtypes in Human Prolactinomas.
P. Jaquet, L. Ouafik, A. Saveanu, G. Gunz, F. Fina, H. Dufour, M. D. Culler, J. P. Moreau, and A. Enjalbert (1999)
J. Clin. Endocrinol. Metab. 84, 3268-3276
   Abstract »    Full Text »
Colocalization of Somatostatin Receptor sst5 and Insulin in Rat Pancreatic {beta}-Cells.
S. W. Mitra, E. Mezey, B. Hunyady, L. Chamberlain, E. Hayes, F. Foor, Y. Wang, A. Schonbrunn, and J. M. Schaeffer (1999)
Endocrinology 140, 3790-3796
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Receptor-mediated Internalization Is Critical for the Inhibition of the Expression of Growth Hormone by Somatostatin in the Pituitary Cell Line AtT-20.
P. Sarret, D. Nouel, C. Dal Farra, J.-P. Vincent, A. Beaudet, and J. Mazella (1999)
J. Biol. Chem. 274, 19294-19300
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H. Baumeister and W. Meyerhof (2000)
J. Biol. Chem. 275, 28882-28887
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Homo- and Heterodimerization of Somatostatin Receptor Subtypes. INACTIVATION OF sst3 RECEPTOR FUNCTION BY HETERODIMERIZATION WITH sst2A.
M. Pfeiffer, T. Koch, H. Schroder, M. Klutzny, S. Kirscht, H.-J. Kreienkamp, V. Hollt, and S. Schulz (2001)
J. Biol. Chem. 276, 14027-14036
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SST3-selective potent peptidic somatostatin receptor antagonists.
J. C. Reubi, J.-C. Schaer, S. Wenger, C. Hoeger, J. Erchegyi, B. Waser, and J. Rivier (2000)
PNAS 97, 13973-13978
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