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:(DDIPIJ)-Lupine Publishers

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 by Eric Lattmann in DDIPIJ in Lupine Publishers

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.

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