Highly Potent 4-Amino-indolo[2,3-c]azepin-3-one-Containing Somatostatin Mimetics with a Range of sst Receptor Selectivities

The synthesis, biological evaluation, and conformational analysis of 4-amini-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the Nand C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

Publication year:2009

Keywords:3-DIMENSIONAL CONSENSUS STRUCTURE, N-METHYL SCAN; CONFORMATIONAL-ANALYSIS, MOLECULAR-MECHANICS, NONPEPTIDE LIGANDS, PHOSPHOLIPASE-C, AGONISTS, NMR, AFFINITY, Biochemistry/biophysics/molecular biology