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

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.

Figure 1

sst 2-Selective leads.

Figure 2

Important analogs of L-054,522.

Figure 3

Superposition of modeled conformations of compound 7 (L-054,522, green) upon cyclic peptide 9 (magenta). Both structures incorporate the available NMR data and have been energy minimized with MMFF94(s).

Figure 4

Receptor subtype potencies of somatostatin and several important analogs.

Figure 5

Inhibition of forskolin-stimulated cAMP accumulation. cAMP accumulation in forskolin-stimulated mouse L cells stably transfected with sst2 was measured in the presence of increasing concentrations of somatostatin-14 or L-054,522. Each point is the average of three determinations, replicate experiments gave similar results.

Figure 6

Plasma GH levels were measured every 10 min for a 24-hr period. At 1300 hr the animals were infused with either L-054,522 (50 μg/kg per hr) or vehicle (0.25% dimethyl sulfoxide) for 11 hr. Replicate experiments gave similar results.