Discovery of highly potent and neurotensin receptor 2 selective neurotensin mimetics.

The neurotensin receptor subtype 2 (NTS2) is involved in the modulation of tonic pain sensitivity and psychiatric diseases and is, therefore, regarded as a highly attractive pharmacological target protein. Aiming to discover NTS2 selective ligands, we herein describe the identification of screening hits and the chemical synthesis of structural variants leading to the highly potent and NTS2 selective peptide-peptoid hybrids of type 3. The neurotensin mimetics 3a and 3e-g incorporating an N-(4-hydroxyphenethyl)glycine substructure exhibit single digit nanomolar affinity (K(i) = 4.3-8.8 nM) and 1900-12000 fold selectivity over the neurotensin receptor subtype 1 (NTS1). According to functional experiments, the test compounds 3a and 3e-g displayed an inhibition of constitutive mitogen-activated protein kinase (MAPK) activity exceeding 2.6-4.6 times the inverse agonist activity of the endogenous ligand neurotensin.