Ligand design for somatostatin receptor isoforms 4 and 5
Murphy, Paul V.
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Negi, Arvind, Zhou, Jian, Sweeney, Sinclair, & Murphy, Paul V. (2019). Ligand design for somatostatin receptor isoforms 4 and 5. European Journal of Medicinal Chemistry, 163, 148-159. doi: https://doi.org/10.1016/j.ejmech.2018.11.030
The somatostatin receptor (SSTR) isoforms, SSTR-4 and SSTR-5 are targets in numerous disorders and diseases. Although there has been some success in achieving selective isoform inhibition, structure-based drug design and development in this area has faced a challenge, mainly attributed to the lack of availability of SSTR-4 and SSTR-5 crystal structures. Previous structure activity relationship (SAR) studies have included work on non-peptide peptidomimetics or Î²-turn peptidal peptidomimetics where side chains of lysine, tryptophan, and phenylalanine (i.e. functional epitopes) are presented on a scaffold or molecular framework. However, there could be more structural information that would help design ligands selective for one or more of these isoforms. Here, we include synthesis of new mimetics and include their evaluation as ligands for SSTR-4 and SSTR-5. Inhibitors based on small to larger sized scaffolds (ManNAc, iminosugars, Eannaphane macrocycles, acyclic and cyclised peptide structures) are compared. These scaffolds have been grafted with side chains of lysine, tryptophan, and phenylalanine or similar bioisosteres/pharmacophoric groups. A new macrocycle as well as an iminosugar derivative show 5-fold or greater selectivity for SSTR-4 over SSTR-5. A new glycopeptide presenting GlcNAc showed â ¼6 fold selectivity for SSTR-5, which contrasted with the non-glycosylated peptide. A number of non-peptide dual inhibitors (Ki values of 0.58â ¯Î¼M to 5â ¯Î¼M) were also identified. Conceivable molecular interactions of these inhibitors were studied with newly constructed homology models of SSTR-4 and SSTR-5 isoforms.