Analgesic Effects of 5-Alkyloxy-4-amino-2(5H)-furanones as Cholecystokinin-2 Antagonists

• Published in: Archiv der Pharmazie (Weinheim) Vol. 349; no. 6; pp. 456 - 465
• Main Authors: Lattmann, Eric, Sattayasai, Jintana, Schwalbe, Carl H., Boonprakob, Yodchai, Dunn, Simon, Fajana, Feyisayo, Lattmann, Pornthip
• Format: Journal Article
• Language: English
• Published: Germany Blackwell Publishing Ltd 01-06-2016; Wiley Subscription Services, Inc
• Subjects: 2(5H)-Furanones; Analgesia potentiation; Animals; CCK antagonists; Desipramine - pharmacology; Drug Synergism; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Guinea Pigs; Isolated tissue preparations; Mice; Morphine - pharmacology; Narcotics; Pain Measurement - drug effects; Radioligand Assay; Radioligand binding; Receptor, Cholecystokinin B - antagonists & inhibitors; Rodents; Structure-Activity Relationship; Tramadol - pharmacology; 2(5H)-Furanones; Analgesia potentiation; Isolated tissue preparations; Radioligand binding; CCK antagonists
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201600036

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.
4‐Amino‐2(5H)‐furanones were synthesized and screened in a [125]I‐CCK‐8 radioligand receptor binding assay for CCK2 affinity. SAR optimization led to furanone 18 (IC50 = 85 nM). It was confirmed as antagonist in the isolated guinea pig ileum assay and it was found to potentiate analgesia in the tail flick assay in mice, with morphine, tramadol, and desimipramine at 0.5 mg/kg.