Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2

  • Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10836-41. doi: 10.1073/pnas.95.18.10836.
L Yang  1 ,  S C Berk ,  S P Rohrer ,  R T Mosley ,  L Guo ,  D J Underwood ,  B H Arison ,  E T Birzin ,  E C Hayes ,  S W Mitra ,  R M Parmar ,  K Cheng ,  T J Wu ,  B S Butler ,  F Foor ,  A Pasternak ,  Y Pan ,  M Silva ,  R M Freidinger ,  R G Smith ,  K Chapman ,  J M Schaeffer ,  A A Patchett
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
PMID: 9724791 DOI: 10.1073/pnas.95.18.10836
Abstract

A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to Somatostatin Receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated Adenylate Cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 microgram/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054, 522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.

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