Novel long-acting somatostatin analog with endocrine selectivity: Potent suppression of growth hormone but not of insulin

Somatostatin, also known as somatotropin release-inhibiting factor (SRIF), is a natural cyclic peptide inhibitor of pituitary, pancreatic, and gastroi ntestinal secretion. Its long-acting analogs are in clinical use for treatm ent of various endocrine syndromes and gastrointestinal anomalies. These an alogs are more potent inhibitors of the endocrine release of GH, glucagon, and insulin than the native SRIF; hence, they do not display considerable p hysiological selectivity. Our goal was to design effective and physiologica lly selective SRIF analogs with potential therapeutic value. We employed an integrated approach consisting of screening of backbone cyclic peptide lib raries constructed on the basis of molecular modeling of known SRIF agonist s and of high throughput receptor binding assays with each of the five clon ed human SRIF receptors (hsst1-5). By using this approach, we identified a novel, high affinity, enzymatically stable, and long-acting SRIF analog, PT R-3173, which binds with nanomolar affinity to human SRIF receptors hsst2, hsst4, and hsst5. The hsst5 and the rat sst5 (rsst5) forms have the same na nomolar affinity for this analog. In the human carcinoid-derived cell line BON-1, PTR-3173 inhibits forskolin-stimulated cAMP accumulation as efficien tly as the drug octreotide, indicating its agonistic effect in this human c ell system. In hormone secretion studies with rats, we found that PTR-3173 is 1000-fold and more than 10,000-fold more potent in inhibiting GH release than glucagon and insulin release, respectively. These results suggest tha t PTR-3173 is the first highly selective somatostatinergic analog for the i n vivo inhibition of GK secretion, with minimal or no effect on glucagon an d insulin release, respectively.