Differential efficacies of somatostatin receptor agonists for G-protein activation and desensitization of somatostatin receptor subtype 4-mediated responses.

Although desensitization represents an important physiological feedback mechanism that protects against overstimulation, it can significantly limit the therapeutic usefulness of drugs. In the current investigation, we have employed Cytosensor microphysiometry for the purpose of determining the propensity of somatostatin receptor agonists to induce desensitization of the human somatostatin receptor subtype 4 (h sst4)-mediated extracellular acidification rate (EAR) response in intact Chinese hamster ovary (CHO) cells. We have compared this propensity with the efficacies of the agonists as measured in a [35S]guanosine-5'-O-(3-thio)triphosphate binding assay with membranes of the same CHO-h sst4 cell line. We observed that (1'S,2S)-4-amino-N-(1'-carbamoyl-2'-phenylethyl)-2-(4''-methyl-1''-naphthalenesulfonylamino)butanamide (J-2156), a superagonist at the h sst4 with higher efficacy than somatostatin-14 itself (Engström et al., 2005), was considerably less prone to cause desensitization of the EAR response than somatostatin-14, somatostatin-28, and cortistatin-17. In contrast, compound A (methyl (2S)-5-{[amino(imino)methyl]amino}-2-{[4-[5-7-difluoro-2-phenyl-1H-indol-3-yl)butanoyl]amino}-pentanoate), which we also found to be an h sst(4) superagonist, albeit to a lesser degree than J-2156, demonstrated a high propensity to cause desensitization. Our results indicate that there is no relationship between the efficacy of the agonists to cause G-protein activation and their ability to induce desensitization of the h sst4-mediated EAR responses. The finding that on the h sst4, J-2156 is not only a superagonist but also shows a low propensity to cause desensitization, might offer therapeutic advantages. At a minimum, the compound will be a powerful tool to study the mechanisms connected to efficacy and desensitization of h sst4-mediated responses.