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

J Med Chem. 2018 Aug 23;61(16):7103-7115. doi: 10.1021/acs.jmedchem.8b00175. Epub 2018 Aug 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Non-Narcotic / chemistry*
  • Analgesics, Non-Narcotic / pharmacology*
  • Animals
  • Binding, Competitive
  • Blood Pressure / drug effects
  • Body Temperature / drug effects
  • CHO Cells
  • Cricetulus
  • Cyclization
  • Drug Evaluation, Preclinical / methods
  • Drug Stability
  • Male
  • Molecular Docking Simulation
  • Neurotensin / agonists
  • Neurotensin / chemistry
  • Neurotensin / pharmacology*
  • Peptide Fragments / agonists
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology*
  • Peptides, Cyclic / blood
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / pharmacology
  • Rats, Sprague-Dawley
  • Receptors, Neurotensin / chemistry
  • Receptors, Neurotensin / metabolism*
  • Structure-Activity Relationship
  • Tyrosine / chemistry

Substances

  • Analgesics, Non-Narcotic
  • Peptide Fragments
  • Peptides, Cyclic
  • Receptors, Neurotensin
  • neurotensin type 1 receptor
  • Neurotensin
  • Tyrosine
  • neurotensin (8-13)