Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry.
Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.
Rohrer
S P
SP
Department of Cell Biochemistry and Physiology, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA. susanvrohrer@merck.com
Birzin
E T
ET
Mosley
R T
RT
Berk
S C
SC
Hutchins
S M
SM
Shen
D M
DM
Xiong
Y
Y
Hayes
E C
EC
Parmar
R M
RM
Foor
F
F
Mitra
S W
SW
Degrado
S J
SJ
Shu
M
M
Klopp
J M
JM
Cai
S J
SJ
Blake
A
A
Chan
W W
WW
Pasternak
A
A
Yang
L
L
Patchett
A A
AA
Smith
R G
RG
Chapman
K T
KT
Schaeffer
J M
JM
D000577:Amides / Q000378:metabolism / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D015195:Drug Design; D005934:Glucagon / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008565:Membrane Proteins; D051379:Mice; D008956:Models, Chemical; D008969:Molecular Sequence Data; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000502:physiology
D000577:Amides; D007328:Insulin; D008024:Ligands; D008565:Membrane Proteins; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C098681:somatostatin receptor subtype-4; C101130:somatostatin receptor type 1; C094573:somatostatin receptor 5; D013006:Growth Hormone; D005934:Glucagon; C093733:somatostatin receptor 2