RT Journal Article
SR Electronic
T1 Superagonism at the Human Somatostatin Receptor Subtype 4
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 332
OP 338
DO 10.1124/jpet.104.075531
VO 312
IS 1
A1 Mia Engström
A1 Jussi Tomperi
A1 Kamel El-Darwish
A1 Mikaela Åhman
A1 Juha-Matti Savola
A1 Siegfried Wurster
YR 2005
UL http://jpet.aspetjournals.org/content/312/1/332.abstract
AB We have discovered a novel compound, J-2156 [(1′S, 2S)-4-amino-N-(1′-carbamoyl-2′-phenylethyl)-2-(4″-methyl-1″-naphthalenesulfonylamino)butanamide], that belongs to a new class of somatostatin receptor ligands. J-2156 binds with nanomolar affinity to the human somatostatin receptor subtype 4 and is over 400-fold subtype-selective against the other somatostatin receptors. When evaluated in a [35S]guanosine-5′-O-(3-thio) triphosphate binding assay, J-2156 elicited a response 2 to 3 times as large as that of somatostatin-28 and somatostatin-14. That somatostatin-14 is clearly not a maximally efficacious agonist could be verified by demonstrating that it displays the typical behavior of a partial agonist when tested against J-2156. Increasing concentrations of somatostatin-14 cause a concentration-dependent rightward shift of the dose-response curves for J-2156, without affecting its maximal response. This lack of reduction of the maximal response and the fact that the superior efficacy of J-2156 is detected in membranes argue against desensitization and internalization as possible explanations for the superior efficacy of J-2156. More likely is that somatostatin-14 and J-2156 stabilize distinct receptor conformations that differ in their ability to interact with G-proteins. In a cyclic AMP assay, J-2156, somatostatin-28, and somatostatin-14 all act as full agonists. However, this outcome is most likely due to the presence of a receptor reserve in the cyclic AMP assay since there is a large gain of apparent potency in the cyclic AMP assay and the gain is larger for J-2156 than for somatostatin. We conclude that the endogenous ligands somatostatin-14 and somatostatin-28 do not define maximal agonism on the human somatostatin receptor subtype 4 and that J-2156 represents a so-called superagonist. The American Society for Pharmacology and Experimental Therapeutics