Chemistry and Pharmacology of SMS 201-995, a Long-Acting Octapeptide Analogue of Somatostatin

Abstract

Pless J, Bauer W, Briner U, Doepfner W, Marbach P, Maurer R, Petcher TJ, Reubi J-C, Vonderscher J. Chemistry and pharmacology of SMS 201-995, a long-acting octapeptide analogue of somatostatin.

Starting from a hypothetical conformation of natural somatostatin and a knowledge of the minimal fragment needed for biological activity, a process of rational design and lead optimization has led to the potent, selective, and long-acting analogue SMS 201-995

DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr(ol)

which selectively inhibits growth hormone secretion in several animal species for up to 6 h after subcutaneous application. In the rat, SMS inhibits GH, insulin, and glucagon 70, 3, and 23 times more potently than SRIF, resulting in GH/insulin and GH/glucagon selectivities of 20 and 3, respectively. The compound has been shown to inhibit growth of transplantable insulinomas in hamsters and to label selectively a subset of somatostatin receptors in the rat cortex. A radioactively labelled analogue has been used to visualize somatostatin receptors in a GRF-secreting human tumour. The stability and duration of action of SMS 201-995 after subcutaneous injection enable for the first time extended investigations of the clinical utility of somatostatin in various diseases.

Key Words:

• Autoradiography
• binding studies
• growth hormone selectivity
• long-acting
• metabolic stability
• octapeptide
• rational design
• somatostatin
• turnour growth