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Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog
Pharmacodynamic and pharmacokinetic profiles of a neurotensin receptor type 2 (NTS2) analgesic macrocyclic analog
- Source :
- Biomedicine & Pharmacotherapy, Vol 141, Iss, Pp 111861-(2021), Biomedicine and Pharmacotherapy, Biomedicine and Pharmacotherapy, 2021, 141, pp.111861. ⟨10.1016/j.biopha.2021.111861⟩
- Publication Year :
- 2021
-
Abstract
- International audience; The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys8 and Trp11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (Ki 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t1/2 > 24 h) compared with NT (t1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED50 = 4.6 µg/kg) and tonic (ED50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain.
- Subjects :
- Male
Macrocyclic Compounds
Opioid-sparing effects
Analgesic
Pain
RM1-950
CHO Cells
Pharmacology
Substrate Specificity
Rats, Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Cricetulus
Cricetinae
medicine
Animals
Receptors, Neurotensin
Neurotensin receptor
Receptor
ED50
030304 developmental biology
Pain Measurement
Inflammation
0303 health sciences
Dose-Response Relationship, Drug
Morphine
Chemistry
Proteolytic enzymes
Drug Synergism
General Medicine
Analgesics, Non-Narcotic
Rats
[SDV.TOX] Life Sciences [q-bio]/Toxicology
Analgesics, Opioid
Opioid
Macrocycle
Cyclization
Hyperalgesia
[SDV.TOX]Life Sciences [q-bio]/Toxicology
Drug Design
Metabolic stability
Therapeutics. Pharmacology
Analgesia
030217 neurology & neurosurgery
medicine.drug
Neurotensin
Subjects
Details
- ISSN :
- 19506007 and 07533322
- Volume :
- 141
- Database :
- OpenAIRE
- Journal :
- Biomedicinepharmacotherapy = Biomedecinepharmacotherapie
- Accession number :
- edsair.doi.dedup.....5ab23a033cba3c401f41128a4191afd5
- Full Text :
- https://doi.org/10.1016/j.biopha.2021.111861⟩