Drug design at peptide receptors - Somatostatin receptor ligands

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 (sst(1-5)) belong to the G-protein coupled/heptathelical receptor family. Structural and operational features distinguish two classes of receptors; SRIF1 - sst(1)/sst(3)/sst(5) (high affinity for octreotide or seglitide) and SRIF2 = 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., [I-125]LTT-SRIF28, [I-125]CGP23996, [I-125]Tyr(10)cortistatin or [I-125]Tyr(11)SRIF(14). In contrast, [I-125]Tyr(3)octreotide, [I-125]BIM23027, [I-125]MK678 or [I-125]D-Trp(8)SRIF(14) label predominantly SRIF1 sites, especially sst(2) and possibly sst(5) receptors. In brain, [I-125]Tyr(3)octreotide binding equates with sst(2) receptor mRNA distribution. Native SRIF2 receptors can be labeled with [I-125]SRIF14 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) (L757,519), sst(2) (L779,976), sst(3) (L796,77/8), sst(4) (NNC26-9100, L803,087) or sst(1)/sst(5) receptors (L817,018). 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.