Frederick W. Holly

Highly active cyclic and bicyclic somatostatin analogues of reduced ring size

THE biological activity of an organic compound represents the sum of several properties, including solubility, absorption, transport, plasma protein binding, metabolism and receptor binding. The degree of molecular flexibility may affect these properties in different ways. Our approach to the design of somatostatin analogues with reduced susceptibility to metabolic inactivation has been both to eliminate those amino acids which are not required for biological activity and to increase the rigidity of the molecule. We report here the preparation of conformationally constrained analogues of somatostatin (Fig. 1, IIa and III) which are highly active inhibitors of the release of insulin, glucagon and growth hormone in vivo. Analogue III (Fig. 1), which retains only four of the amino acids of the natural hormone (sequence 7–10), is relatively resistant to the action of trypsin in vitro.