title: Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2.
abstract: A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 microgram/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054, 522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.forename: S C
authors.initials: SC
authors.lastname: Berk
authors.forename: S P
authors.initials: SP
authors.lastname: Rohrer
authors.forename: R T
authors.initials: RT
authors.lastname: Mosley
authors.forename: L
authors.initials: L
authors.lastname: Guo
authors.forename: D J
authors.initials: DJ
authors.lastname: Underwood
authors.forename: B H
authors.initials: BH
authors.lastname: Arison
authors.forename: E T
authors.initials: ET
authors.lastname: Birzin
authors.forename: E C
authors.initials: EC
authors.lastname: Hayes
authors.forename: S W
authors.initials: SW
authors.lastname: Mitra
authors.forename: R M
authors.initials: RM
authors.lastname: Parmar
authors.forename: K
authors.initials: K
authors.lastname: Cheng
authors.forename: T J
authors.initials: TJ
authors.lastname: Wu
authors.forename: B S
authors.initials: BS
authors.lastname: Butler
authors.forename: F
authors.initials: F
authors.lastname: Foor
authors.forename: A
authors.initials: A
authors.lastname: Pasternak
authors.forename: Y
authors.initials: Y
authors.lastname: Pan
authors.forename: M
authors.initials: M
authors.lastname: Silva
authors.forename: R M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: R G
authors.initials: RG
authors.lastname: Smith
authors.forename: K
authors.initials: K
authors.lastname: Chapman
authors.forename: J M
authors.initials: JM
authors.lastname: Schaeffer
authors.forename: A A
authors.initials: AA
authors.lastname: Patchett
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007329:Insulin Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018716:Molecular Mimicry; D051381:Rats; D017481:Receptors, Somatostatin / Q000819:agonists*
chemical_list: D001562:Benzimidazoles; D007211:Indoles; D007328:Insulin; D007329:Insulin Antagonists; C114420:L 054522; D017481:Receptors, Somatostatin; D013006:Growth Hormone; D005934:Glucagon; C093733:somatostatin receptor 2