Journal
ACS CHEMICAL NEUROSCIENCE
Volume 10, Issue 11, Pages 4535-4544Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.9b00390
Keywords
Neurotensin peptides; receptor selectivity; unnatural amino acids; GPCR ligands; NTS2; analgesia
Funding
- Canadian Institute of Health Research (CIHR) [FDN-148413]
- CIHR [MOP-123399, MOP-136871]
- Fonds de la Recherche Quebec Sante
- Institut de Pharmacologie de Sherbrooke
- Fonds de Recherche du Quebec en Sante (FRQ-S)
- Research Foundation Flanders (FWO Vlaanderen)
- Research Council (OZR) of the Vrije Universiteit Brussel (VUB)
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Neurotensin (NT) exerts its analgesic effects through activation of the G protein-coupled receptors NTS1 and NTS2. This opioid-independent antinociception represents a potential alternative for pain management. While activation of NTS1 also induces a drop in blood pressure and body temperature, NTS2 appears to be an analgesic target free of these adverse effects. Here, we report modifications of NT at Tyr(11) to increase selectivity toward NTS2, complemented by modifications at the N-terminus to impair proteolytic degradation of the biologically active NT(8-13) sequence. Replacement of Tyr(11) by either 6-OH-Tic or 7-OH-Tic resulted in a significant loss of binding affinity to NTS1 and subsequent NTS2 selectivity. Incorporation of the unnatural amino acid beta(3)hLys at position 8 increased the half-life to over 24 h in plasma. Simultaneous integration of both beta(3)hLys(8) and 6-OH-Tic(11) into NT(8-13) produced a potent and NTS2-selective analogue with strong analgesic action after intrathecal delivery in the rat formalin-induced pain model with an ED(50 )of 1.4 nmol. Additionally, intravenous administration of this NT analogue did not produce persistent hypotension or hypothermia. These results demonstrate that NT analogues harboring unnatural amino acids at positions 8 and 11 can enhance crucial pharmacokinetic and pharmacodynamic features for NT(8-13) analogues, i.e., proteolytic stability, NTS2 selectivity, and improved analgesic/adverse effect ratio.
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