title: Superagonism at the human somatostatin receptor subtype 4.
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 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.
authors.affiliation: Juvantia Pharma Ltd., Lemminkäisenkatu 5, FIN-20520 Turku, Finland. mia.engstrom@juvantia.com
authors.forename: Mia
authors.initials: M
authors.lastname: Engström
authors.forename: Jussi
authors.initials: J
authors.lastname: Tomperi
authors.forename: Kamel
authors.initials: K
authors.lastname: El-Darwish
authors.forename: Mikaela
authors.initials: M
authors.lastname: Ahman
authors.forename: Juha-Matti
authors.initials: JM
authors.lastname: Savola
authors.forename: Siegfried
authors.initials: S
authors.lastname: Wurster
mesh_terms: D000818:Animals; D002073:Butanes / Q000138:chemical synthesis / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008565:Membrane Proteins; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000819:agonists*; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D002073:Butanes; D008565:Membrane Proteins; D009281:Naphthalenes; D017481:Receptors, Somatostatin; D013450:Sulfones; C098681:somatostatin receptor subtype-4; C499293:(1'S, 2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide