Superagonism at the human somatostatin receptor subtype 4

The Journal of Pharmacology and Experimental Therapeutics
Mia EngströmSiegfried Wurster

Abstract

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 [(35)S]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 diff...Continue Reading

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Citations

May 16, 2006·European Journal of Pharmacology·Katalin SándorZsuzsanna Helyes
Aug 16, 2015·British Journal of Pharmacology·R SchrageK Mohr
Apr 27, 2005·British Journal of Pharmacology·Juha R SavinainenJarmo T Laitinen
Oct 16, 2012·British Journal of Pharmacology·R SchrageK Mohr
Feb 23, 2011·Natural Product Reports·Charles R RobertsonGrzegorz Bulaj
Dec 15, 2019·International Journal of Molecular Sciences·Boglárka KántásZsuzsanna Helyes

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