1. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry.
- Author
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Rohrer SP, Birzin ET, Mosley RT, Berk SC, Hutchins SM, Shen DM, Xiong Y, Hayes EC, Parmar RM, Foor F, Mitra SW, Degrado SJ, Shu M, Klopp JM, Cai SJ, Blake A, Chan WW, Pasternak A, Yang L, Patchett AA, Smith RG, Chapman KT, and Schaeffer JM
- Subjects
- Amides metabolism, Amino Acid Sequence, Animals, Cell Line, Cells, Cultured, Cricetinae, Drug Design, Glucagon metabolism, Growth Hormone metabolism, Insulin metabolism, Insulin Secretion, Islets of Langerhans drug effects, Islets of Langerhans metabolism, Ligands, Membrane Proteins, Mice, Models, Chemical, Molecular Sequence Data, Pituitary Gland, Anterior drug effects, Pituitary Gland, Anterior metabolism, Rats, Receptors, Somatostatin physiology, Amides pharmacology, Receptors, Somatostatin agonists
- Abstract
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.
- Published
- 1998
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