NTS2-selective neurotensin mimetics with tetrahydrofuran amino acids

Stimulation of the NTS2 neurotensin receptor causes antipsychotic effects and leads to a promotion of the μ-opioid-independent antinociception, which is important in the modulation of tonic pain sensitivity. We report the synthesis and properties of a small library of peptidic agonists based on the active neurotensin fragment NT(8-13). Two tetrahydrofuran amino acid derivatives were synthesized to replace Tyr¹¹ in NT(8-13). Additionally, Arg⁸, Arg⁹, and Ile¹² of the lead peptide were exchanged by Lys, Lys, and Gly, respectively. The new compounds showed substantial NTS2 binding affinity and up to 1000-fold selectivity over NTS1. The highest selectivity (K_i(NTS2): 29nM, K_i(NTS1): 35,000nM) was observed for the peptide analog 17R^trans.