From Merck’s CCK- Antagonists Via 4-Amino-2(5H)-
Furanones towards 5-Hydroxy-Pyrrol-2-Ones:
Design, Synthesis and Evaluation of PNB-001 & PNB-081
as Experimental Therapeutic Agents in Pain Management
Volume 1 - Issue 1
Eric Lattmann1*, JintanaSattayasai2, Ramesh Narayanan3, Julian Benyamen1, PN Balaram4 and Pornthip
Lattmann4
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- 1School of Life and Health Sciences, Aston University, England
- 2Department of Pharmacology, KhonKaen University, Thailand
- 3Department of Medicine, University of Tennessee Health Science Center, USA
- 4PNB Vesper Life Science PVT, India
*Corresponding author:
Eric Lattmann, School of Life and Health Sciences, Aston University, England
Received: March 20, 2018; Published: March 27, 2018
DOI: 10.32474/DDIPIJ.2018.01.000105
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Abstract
Arylated 5-hydroxy–pyrrol-2-ones were prepared in 2 synthetic steps from muco-chloric acid and were optimised as CCK1 /
CCK2 selective ligands using radio labelled binding assays. A potent CCK1 selective ligand was identified (PNB-081: CCK1=20nM)
as well as a potent CCK2 ligand (PNB-001, IC50= 22nM) during a systematic SAR optimisation. The antagonism was confirmed for
both ligands by using isolated tissue preparations with CCK5 and CCK8S. Subsequent in vivo evaluation revealed analgesic activity
for the gastrin CCK2 antagonist PNB-001, in the hotplate and tail immersion test at 0.5mg /kg by IP administration in mice. The
cholecystokinin antagonist PNB-081 potentiated the analgesic effect of morphine and reversed opiate tolerance in mice from doses
>1 mg/kg by oral administration.
Keywords: Phenyl-Pyrolone; CCK Antagonist; Cholecystokinin; Analgesic; Opiate Adjunct
Abbrevations: GIT: Gastrointestinal Tract; TT: Test Thresholds; BT: Base Line Withdrawal Thresholds; ANOVA: Analysis Of
Variance
Abstract|
Introduction|
Results and Discussions|
Pharmacology|
Conclusion|
Experimental Section|
DMolecular Modelling|
Acknowledgement|
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