Structural Optimization and Characterization of Potent Analgesic Macrocyclic Analogues of Neurotensin (8–13)

The
neurotensin receptors are attractive targets for the development
of new analgesic compounds. They represent potential alternatives
or adjuvants to opioids. Herein, we report the structural optimization
of our recently reported macrocyclic peptide analogues of NT(8–13).
The macrocycle was formed via ring-closing metathesis (RCM) between
an ortho allylated tyrosine residue in position 11
and the side chain of alkene-functionalized amino acid in position
8 of NT(8–13). Minute modifications led to significant binding
affinity improvement (Ki improved from
5600 to 15 nM) with greatly improved plasma stability compared to
NT(8–13). This study also delineates the structural features
influencing these parameters. The signaling profiles of the new macrocycles
were determined on the NTS1 receptor, and the physiological effects
of the two most potent and stable analogues were assessed in vivo
using rodent models. Both compounds displayed strong analgesic effects.