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 () 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.
Bibliographical noteThis is the peer reviewed version of the following article: Lattmann, E., Sattayasai, J., Schwalbe, C. H., Boonprakob, Y., Dunn, S., Fajana, F., & Lattmann, P. (2016). Analgesic effects of 5-alkyloxy-4-amino-2(5H)-furanones as cholecystokinin-2 antagonists. Archiv der Pharmazie, 349(6), 456-465, which has been published in final form at http://dx.doi.org/10.1002/ardp.201600036. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
- analgesia potentiation
- CCK antagonists
- isolated tissue preparations
- radioligand binding