Drug design at peptide receptors: somatostatin receptor ligands

J Mol Neurosci. 2002 Feb-Apr;18(1-2):15-27. doi: 10.1385/JMN:18:1-2:15.


Somatostatin (SRIF, somatotropin release inhibiting factor), discovered for its inhibitory action on growth hormone (GH) secretion from pituitary, is an abundant neuropeptide. Two forms, SRIF14 and SRIF28 exist. Recently, a second family of peptides with very similar sequences and features was described; the cortistatins (CST), CST17 and CST29 which are brain selective. The five cloned SRIF receptors (sst1-5) belong to the G-protein coupled/ heptathelical receptor family. Structural and operational features distinguish two classes of receptors; SRIF1 - sst2/sst3/sst5 (high affinity for octreotide or seglitide) and SRIF2 = sst1/sst4(very low affinitty for the aforementioned ligands). The affinity of SRIF receptors for somatostatins and cortistatins is equally high, and it is not clear whether selective receptors do exist for one or the other of the peptides. Several radiologlands label all SRIF receptors, e.g., [125]LTT-SRIF28' [l25I]CGP23996, [125]Tyr10cortistatin or [125I]Tyr11SRIF14. In contrast, [125I]Tyr3octreotide, [125I]BIM23027, [125I]MK678 or [125I]D-Trp8SRIF14 label predominantly SRIF1 sites, especially sst2 and possibly sst5 receptors. In brain, [125I]Tyr3octreotide binding equates with sst2 receptor mRNA distribution. Native SRIF2receptors can be labeled with [125I]SRIF14 in the presence of high NaCl in brain (sst1) or lung (sst4) tissue. Short cyclic or linear peptide analogs show selectivity for sst2/sst5 (octreotide, lanreotide, BIM 23027), sst1 (CH-275), sst3 (sst3-ODN-8), or sst5 receptors (BIM 23268); although claims for selectivity have not always been confirmed. Beta peptides ith affinity for SRIF receptors are also reported. The general lack of SRIF receptor antagonists is unique for peptide receptors, although CYN 154806 is a selective and potent sst2 antagonist. Nonpeptide ligands are still rare, although a number of molecules have been reported with selectivity and potency for sst1 (L 757,519), sst2 (L 779,976), sst3 (L 796,778), sst4 (NNC 26-9100, L 803,087) or sst1/sst5 receptors (L 817,018). Such molecules are essential to establish the role of SRIF receptors, e.g., sst1 in hypothalamic glutamate currents: sst2 in inhibiting release of GH, glucagon, TSH, gastric acid secretion, pain, seizures and tumor growth, and sst5 in vascular remodeling and inhibition of insulin and GH release.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Binding, Competitive / drug effects
  • Binding, Competitive / physiology
  • Brain / drug effects
  • Brain / metabolism*
  • Drug Design*
  • Humans
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism*
  • Ligands
  • Neuropeptides / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptors, Somatostatin / agonists*
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / metabolism
  • Somatostatin / analogs & derivatives*
  • Somatostatin / metabolism


  • Ligands
  • Neuropeptides
  • Peptide Fragments
  • Receptors, Somatostatin
  • cortistatin
  • Somatostatin