Drug design at peptide receptors

Somatostatin (SRIF, somatotropin release inhibiting factor), discovered for its inhibitory action on growth hormone (GH) secretion from pituitary, is an abundant neuropeptide. Two forms, SRIF 14 and SRIF 28 exist. Recently, a second family of peptides with very similar sequences and features was described; the cortistatins (CST), CST 17 and CST 29 which are brain selective. The five cloned SRIF receptors (sst 1–5 ) belong to the G-protein coupled/heptathelical receptor family. Structural and operational features distinguish two classes of receptors; SRIF 1 -sst 2 /sst 3 /sst 5 (high affinity for octreotide or seglitide) and SRIF 2 =sst 1 /sst 4 (very low affinity 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 I]LTT-SRIF 28 , [ 125 I]CGP23996, [ 125 I]Tyr 10 cortistatin or [ 125 I]Tyr 11 SRIF 14 . In contrast, [ 125 I]Tyr 3 octreotide, [ 125 I]BIM23027, [ 125 I]MK678 or [ 125 I]D-Trp 8 SRIF 14 label predominantly SRIF 1 sites, especially sst 2 and possibly sst 5 receptors. In brain, [ 125 I]Tyr 3 octreotide binding equates with sst 2 receptor mRNA distribution. Native SRIF 2 receptors can be labeled with [ 125 I]SRIF 14 in the presence of high NaCl in brain (sst 1 ) or lung (sst 4 ) tissue. Short cyclic or linear peptide analogs show selectivity for sst 2 /sst 5 (octreotide, lanreotide, BIM 23027), sst 1 (CH-275), sst 3 (sst 3 -ODN-8), or sst 5 receptors (BIM 23268); although claims for selectivity have not always been confirmed. Beta peptides with 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 sst 2 antagonist. Nonpeptide ligands are still rare, although a number of molecules have been reported with selectivity and potency for sst 1 (L 757,519), sst 2 (L 779,976), sst 3 (L 796,778), sst 4 (NNC 26-9100, L 803,087) or sst 1 /sst 5 receptors (L 817,018). Such molecules are essential to establish the role of SRIF receptors, e.g., sst 1 in hypothalamic glutamate currents: sst 2 in inhibiting release of GH, glucagon, TSH, gastric acid secretion, pain, seizures and tumor growth, and sst 5 in vascular remodeling and inhibition of insulin and GH release.