Identification and characterization of subtype selective somatostatin receptor agonists

High affinity, subtype selective non-peptide agonists of somatostatin recep tor subtypes 1-5 were identified in combinatorial libraries constructed bas ed on molecular modeling of known peptide agonists. Simultaneous traditiona l chemical synthesis yielded an additional series of somatostatin subtype-2 receptor (SSTR2) selective agonists. These compounds have been used to fur ther define the physiological functions of the individual somatostatin rece ptor subtypes. In vitro experiments demonstrated the role of the SSTR2 in i nhibition of glucagon release from mouse pancreatic alpha -cells and the so matostatin subtype-5 receptor (SSTR5) as a mediator of insulin secretion fr om pancreatic beta -cells. Both SSTR2 and SSTRS regulated growth hormone re lease from the rat anterior pituitary gland. In vivo studies performed with SSTR2 receptor selective compounds demonstrated effective inhibition of pu lsatile growth hormone release in rats. The SSTR2 selective compounds also lowered plasma glucose levels in normal and diabetic animal models. The ava ilability of high affinity, subtype selective non-peptide agonists for each of the somatostatin receptors provides a direct approach to defining their physiological function both peripherally and in the central nervous system . (C) 2000 Elsevier Science Ltd. Published by Editions scientifiques et med icales Elsevier SAS.