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Analgesic Effects of 5‐Alkyloxy‐4‐amino‐2(5 H )‐furanones as Cholecystokinin‐2 Antagonists
Author(s) -
Lattmann Eric,
Sattayasai Jintana,
Schwalbe Carl H.,
Boonprakob Yodchai,
Dunn Simon,
Fajana Feyisayo,
Lattmann Pornthip
Publication year - 2016
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201600036
Subject(s) - chemistry , cholecystokinin , cholecystokinin b receptor , radioligand , agonist , stereochemistry , antagonist , opiate , morphine , partial agonist , analgesic , pharmacology , receptor , biochemistry , biology
4‐Amino‐2(5 H )‐furanones were synthesized in high yields over two synthetic steps from readily available mucochloric acid. These 5‐alkyloxy‐4‐amino‐2(5 H )‐furanones were screened in a [125] I‐CCK‐8 radioligand receptor binding assay for CCK 2 affinity and novel active ligands in the nanomolar range were identified. SAR was optimized leading to the cyclohexyl derivative 25 with an IC 50 of 27 nM. Furanone 18 was obtained as a stable crystalline material with an IC 50 of 85 nM, but had a higher CCK 2 selectivity. It was subsequently tested in the isolated guinea pig ileum assay with sulfated CCK 8 , and the CCK antagonizing properties of the ligand were confirmed. The CCK 2 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.