William J. Paleveda

A super active cyclic hexapeptide analog of somatostatin

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

Synthesis of imidazoles

ConclusionsThe synthesis of 4-alkylimidazoles was carried out by heating (2-oxoalkyl)triethylammonium bromides with formamide.

Synthesis of New Peptides Based on Models of Receptor-Bound Conformation

About three dozen small peptides (mostly 2–40 residues) have been identified in the nervous system (Iversen 1983,1984; Krieger 1983). The neuropeptides mediate a wide range of endocrine, motor, and behavioral responses (Snyder 1980; Krieger 1983). These substances control such diverse functions as growth, reproduction, digestion, metabolism, and the dynamics of the cardiovascular system. Immunostaining techniques have been used to visualize and map the distribution of peptides, in particular neuronal pathways. Many of these substances have also been shown to occur in peripheral regions, such as the gastrointestinal tract. The role of many of these agents is largely unknown, but their potential utility in therapy is great.