Potent, highly selective inhibition of growth hormone secretion by position 4 somatostatin analogs

Aromatic position 4 somatostatin (SS) analogs were synthesized by solid phase methodology and assayed in vivo for their effects on pentobarbital-stimulated GH levels in fed rats and insulin and glucagon levels in fasted rats. [F5-Phe4]SS was approximately 3 times more active than somatostatin in inhibiting all three hormones. [Phe4,D-Trp8]SS inhibited GH about 4 times more effectively than somatostatin and was only twice as active as somatostatin in the pancreas. [rho-NH2-Phe4]SS exhibited strong selectivity toward inhibition of GH, being 4 times more potent than somatostatin in the pituitary while only about 40% as active in the pancreas. [rho-NH2-Phe4,D-Trp8]SS maintained this same degree of selectivity toward GH inhibition and exhibited a striking 15-fold increase in activity in the pituitary compared to somatostatin. All four analogs inhibited GH for a longer period of time than somatostatin when administered sc at a dose of 10 microgram/100 g BW. [rho-NH2-Phe4,D-Trp8]SS was the longest acting of these analogs, with approximately a 2-h duration of inhibition of GH. [Phe4]SS, administered iv at a dose of 50 microgram/100 g BW, also inhibited GH for approximately 2 h. These data further support the feasibility of developing long-acting somatostatin analogs with selectivity toward a given hormone.