Identification and characterization of subtype selective somatostatin receptor agonists.
High affinity, subtype selective non-peptide agonists of somatostatin receptor subtypes 1-5 were identified in combinatorial libraries constructed based on molecular modeling of known peptide agonists. Simultaneous traditional chemical synthesis yielded an additional series of somatostatin subtype-2 receptor (SSTR2) selective agonists. These compounds have been used to further define the physiological functions of the individual somatostatin receptor subtypes. In vitro experiments demonstrated the role of the SSTR2 in inhibition of glucagon release from mouse pancreatic alpha-cells and the somatostatin subtype-5 receptor (SSTR5) as a mediator of insulin secretion from pancreatic beta-cells. Both SSTR2 and SSTR5 regulated growth hormone release from the rat anterior pituitary gland. In vivo studies performed with SSTR2 receptor selective compounds demonstrated effective inhibition of pulsatile growth hormone release in rats. The SSTR2 selective compounds also lowered plasma glucose levels in normal and diabetic animal models. The availability 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.
Rohrer
S P
SP
Department of Endocrinology and Chemical Biology, Merck Research Laboratories, Rahway, NJ 07065, USA. susan_rohrer@merck.com
Schaeffer
J M
JM
D000577:Amides / Q000737:chemistry*; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry; D016466:CHO Cells; D003001:Cloning, Molecular; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D005934:Glucagon / Q000378:metabolism; D007211:Indoles / Q000737:chemistry*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008565:Membrane Proteins; D009281:Naphthalenes / Q000737:chemistry*; D009578:Nitrobenzenes / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D013004:Somatostatin / Q000819:agonists
D000577:Amides; D001562:Benzimidazoles; D007211:Indoles; D007328:Insulin; C114420:L 054522; C121854:L 779976; C121853:L 817818; C429627:L796778; C429626:L797591; C429628:L803087; D008565:Membrane Proteins; D009281:Naphthalenes; D009578:Nitrobenzenes; D011725:Pyridines; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; D013004:Somatostatin; C094573:somatostatin receptor 5; D005934:Glucagon; C093733:somatostatin receptor 2