title: Analgesic Effects of 5-Alkyloxy-4-amino-2(5H)-furanones as Cholecystokinin-2 Antagonists.
abstract: 4-Amino-2(5H)-furanones were synthesized in high yields over two synthetic steps from readily available mucochloric acid. These 5-alkyloxy-4-amino-2(5H)-furanones were screened in a ([125]) I-CCK-8 radioligand receptor binding assay for CCK2 affinity and novel active ligands in the nanomolar range were identified. SAR was optimized leading to the cyclohexyl derivative 25 with an IC50 of 27 nM. Furanone 18 was obtained as a stable crystalline material with an IC50 of 85 nM, but had a higher CCK2 selectivity. It was subsequently tested in the isolated guinea pig ileum assay with sulfated CCK8 , and the CCK antagonizing properties of the ligand were confirmed. The CCK2 selective antagonist 18 was found to potentiate analgesia in the tail flick assay in mice, for the strong opiate morphine, the partial opiate agonist tramadol and the tricyclic antidepressant desimipramine.
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Lattmann
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Jintana
authors.initials: J
authors.lastname: Sattayasai
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Carl H
authors.initials: CH
authors.lastname: Schwalbe
authors.affiliation: Faculty of Medicine, Department of Pharmacology, Khon Kaen University, Khon Kaen, Thailand.
authors.forename: Yodchai
authors.initials: Y
authors.lastname: Boonprakob
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Dunn
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Feyisayo
authors.initials: F
authors.lastname: Fajana
authors.affiliation: The School of Pharmacy, Aston University, Birmingham, UK.
authors.forename: Pornthip
authors.initials: P
authors.lastname: Lattmann
mesh_terms: D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D004357:Drug Synergism; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D011869:Radioligand Assay; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014147:Tramadol / Q000494:pharmacology
chemical_list: D005663:Furans; D043887:Receptor, Cholecystokinin B; D014147:Tramadol; D009020:Morphine; D003891:Desipramine
keywords: 2(5H)-Furanones; Analgesia potentiation; CCK antagonists; Isolated tissue preparations; Radioligand binding