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.

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

“…CCK 2 and CCK 1 receptor binding assays were performed using standard receptor binding assays. 24,25 Male guinea pig brain tissues were prepared according to the modified method described. 28 Pancreatic membranes were prepared as described and binding assays were carried out with L-363, 260 as standard.…”

“…Here, a full biological evaluation of the PNB-cancer molecules towards PNB-101, a potent and selective fluorinated gastrin antagonist will be reported in detail with respect to the anti-neoplastic properties of the molecule, in particular for lung cancer. [19][20][21][22][23][24][25][26][27]…”

Cholecystokinin Antagonists: Fluorinated 5-Hydroxy-5-Aryl-Pyrrol-2-Ones as Experimental Agents for Brain, Colon and Pancreatic Cancer

“…A mixed antagonist may work best for treating brain cancers, as mengionomas express CCK 1 receptors and astrocytomas CCK 2 receptors [25]. A human glioma cell line, U-87 responded to CCK 2 antagonists, [26] occurred higher IC value in contrast to SHSY5Y is a further neuroblastoma human cell line reduced level of CCK expression. Most remarkable for this cell line the best inhibition of growths was obtained cell based, indicating possibly the blockage of other non-CCK pathways.…”

“…Aim of the drug discovery programme, initiated by PNB Vesper Life Sciences, was to systematically design from the 2(5H)furanone scaffold [26] a hydroxyl-pyrrolone scaffold with ligands for both CCK 1 and CCK 2 pathways.…”

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

“…A similar effect is seen for the jejunum on indomethacin induced ulcers and this damage of the GI system was prevented by PNB-001. Analgesic evaluation CCK antagonists potentiate the analgesia of opiates and usually, except for proglumide, have no analgesic effect on their own 25 . For Z-360 an interesting weak analgesic effect in the formalin test was observed 26 .…”