Design, Structural Optimization, and Characterization of the First Selective Macrocyclic Neurotensin Receptor Type 2 Non-opioid Analgesic

Neurotensin (NT)
receptor type 2 (NTS2) represents an attractive
target for the development of new NT-based analgesics. Here, we report
the synthesis and functional in vivo characterization
of the first constrained NTS2-selective macrocyclic NT analog. While
most chemical optimization studies rely on the NT­(8-13) fragment,
we focused on NT­(7-12) as a scaffold to design NTS2-selective macrocyclic
peptides. Replacement of Ile12 by Leu, and Pro7/Pro10 by allylglycine residues followed by cyclization
via ring-closing metathesis led to macrocycle 4, which
exhibits good affinity for NTS2 (50 nM), high selectivity over NTS1
(>100 μM), and improved stability compared to NT­(8-13). In vivo profiling in rats reveals that macrocycle 4 produces potent analgesia in three distinct rodent pain
models, without causing the undesired effects associated with NTS1
activation. We further provide evidence of its non-opioid antinociceptive
activity, therefore highlighting the strong therapeutic potential
of NTS2-selective analogs for the management of acute and chronic
pain.