Metabolically Stable Neurotensin Analogs Exert Potent and Long-Acting Analgesia Without Hypothermia.

Metabolically Stable Neurotensin Analogs Exert Potent and Long-Acting Analgesia Without Hypothermia. Behav Brain Res. 2021 Feb 16;:113189 Authors: Vivancos M, Fanelli R, Besserer-Offroy É, Beaulieu S, Chartier M, Resua-Rojas M, Mona CE, Previti S, Rémond E, Longpré JM, Cavelier F, Sarret P Abstract The endogenous tridecapeptide neurotensin (NT) has emerged as an important inhibitory modulator of pain transmission, exerting its analgesic action through the activation of the G protein-coupled receptors, NTS1 and NTS2. Whereas both NT receptors mediate the analgesic effects of NT, NTS1 activation also produces hypotension and hypothermia, which may represent obstacles for the development of new pain medications. In the present study, we implemented various chemical strategies to improve the metabolic stability of the biologically active fragment NT(8-13) and assessed their NTS1/NTS2 relative binding affinities. We then determined their ability to reduce the nociceptive behaviors in acute, tonic, and chronic pain models and to modulate blood pressure and body temperature. To this end, we synthesized a series of NT(8-13) analogs carrying a reduced amide bond at Lys8-Lys9 and harboring site-selective modifications with unnatural amino acids, such as silaproline (Sip) and trimethylsilylalanine (TMSAla). Incorporation of Sip and TMSAla respectively in positions 10 and 13 of NT(8-13) combined with the Lys8-Lys9 reduced amine bond (JMV5296)...
Source: Behavioural Brain Research - Category: Neurology Authors: Tags: Behav Brain Res Source Type: research