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E u r o S c i C o n C o n f e r e n c e o n
Chemistry
2018
Journal of Organic & Inorganic Chemistry
ISSN 2472-1123
F e b r u a r y 1 9 - 2 0 , 2 0 1 8
P a r i s , F r a n c e
Chemistry 2018
Page 30
T
he development of drugs that can more effectively and safely treat both acute
and chronic pain remains a major unmet challenge in pharmaceutical industry.
Opiate analgesics, such as morphine or fentanyl, continue to be the cornerstone
medication for treating moderate to severe pain, but their use upon chronic
administration suffers from important side-effects such as tolerance, addiction
and hyperalgesia. Several anti-opioid systems have been reported as valuable
targets for blocking opioid-induced hyperalgesia (OIH). Among them, the NPFF
receptors belonging to the GPCR family were recently identified as one of the
keystoneof theopioid-inducedhyperalgesia.Wedeveloped thefirst NPFF-receptor
antagonist (RF9), and its co-administration with opioid analgesics (fentanyl) led to
block the delayed and long lasting paradoxical opioid induced-hyperalgesia and
prevent the development of associated tolerance. However, the dipeptide nature
of RF9 limited its application to sc or iv administration. Based on an extensive SAR
study, we developed a peptidomimetic of RF9 containing novel unnatural amino-
acids. These basic amino acids were obtained through a specific Ru-catalyzed
reduction of tertiary amides to afford in very high yields novel families of chiral
α or β ϒ amino acids exhibiting a large diversity of basic side chains. Obtained
at a gram-scale, these unnatural amino acids are directly suitable for peptide
synthesis in liquid or solid phase. When applied to the development of new ligand
of NPFF receptors, we were able to design and synthesize RF313 as the first orally-
active NPFF receptor antagonist able to reverse opioid-induced hyperalgesia in
several pain models (post-operative pain, neuropathic pain, inflammatory pain).
Active at low dose (1 mg/kg p.o. in rat), RF313 is also able to extend the duration
of the analgesic effect induced by the opiates, opening the way to a promising
therapeutic pathway to treat acute or chronic pain.
Biography
F Bihel has completed his PhD from University of Marseille
(France) and Postdoctoral studies fromHarvardMedical School
and BWH (Boston, MA, USA). He is currently Senior Researcher
and Group Leader at the French National Center for Scientific
Research (CNRS), within the Laboratoire d’Innovation Théra-
peutique (UMR7200 – CNRS/University of Strasbourg). He is a
member of several academic societies and has publishedmore
than 60 papers in reputed journals, and 6 patents. He is an ex-
pert in Medicinal Chemistry, with research programs dedicated
to design and functionalization of innovative molecular scaf-
folds targeting proteins involved in CNS pathologies or cancers.
fbihel@unistra.frNovel orally-active NPFF receptor
antagonists preventing opioid-induced
hyperalgesia during the treatment of
acute or chronic pains
F Bihel
University of Strasbourg - CNRS, France
F Bihel, J Org Inorg Chem 2018, Volume: 4
DOI: 10.21767/2472-1123-C1-001