Design of somatostatin(SRIF)receptor 1-and 4-selective ligands

摘要

SRIF analogs are used in the treatment of a variety of pathological conditions by modulating one or more of five known membrane-associated receptor subtypes(sst_(1-5))and for receptor-targeted scintigraphy and radionuclide therapy.The actual function,distribution and specificity of the different SRIF receptors,however,are still far from being fully understood due,in part,to the lack of potent,labelable and selective agonists and/or antagonists to each receptor.Using SAR,we have designed highly sst_1 and sst_4-selective agonists and sst_3-selective antagonists that are amenable to specific labeling and with binding affinities equal to or higher than that of SRIF-28.We report the primary structures and binding affinities of newly developed mono-and dicyclic sst_(1-)selective and monocyclic sst_4-selective agonists used in the identification of two distinct consensus bioactive conformations described in the following paper.These pharmacophores are different from that reported for sst_2-selective analogs and can accommodate the selective binding of the non-peptide analogs of SRIF agonists.