Superagonism at the human somatostatin receptor subtype 4.

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.

Expression of the H3 receptor in the developing CNS and brown fat suggests novel roles for histamine.

Histamine and histamine receptors have been implicated in signaling mechanisms in developmental processes in the brain and peripheral organs. Pharmacological studies have also implied that the histamine H(3) receptor, in addition to acting as a presynaptic auto- and heteroreceptor in the central nervous system, is active in peripheral tissues. We show that detectable histamine H(3)-receptor expression during development and in adult rat is restricted to specific areas of the brain and to adipocytes and the capillary network in brown adipose tissue. Histamine H(3)-receptor mRNA expression was not detected in other internal organs studied, or in spinal or sympathetic chain ganglia. These results support a histaminergic involvement in brain development through activation of the histamine H(3) receptor and indicate a possible novel involvement of the histamine H(3) receptor as a mediator of the effects of histamine in thermogenesis in brown adipose tissue.