Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2.
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.
Yang
L
L
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
Berk
S C
SC
Rohrer
S P
SP
Mosley
R T
RT
Guo
L
L
Underwood
D J
DJ
Arison
B H
BH
Birzin
E T
ET
Hayes
E C
EC
Mitra
S W
SW
Parmar
R M
RM
Cheng
K
K
Wu
T J
TJ
Butler
B S
BS
Foor
F
F
Pasternak
A
A
Pan
Y
Y
Silva
M
M
Freidinger
R M
RM
Smith
R G
RG
Chapman
K
K
Schaeffer
J M
JM
Patchett
A A
AA
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*
D001562:Benzimidazoles; D007211:Indoles; D007328:Insulin; D007329:Insulin Antagonists; C114420:L 054522; D017481:Receptors, Somatostatin; D013006:Growth Hormone; D005934:Glucagon; C093733:somatostatin receptor 2