Arachidonylsulfonyl derivatives as cannabinoid CB1 receptor and fatty acid amide hydrolase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 19; pp. 3301 - 3303
• Main Authors: Segall, Yoffi, Quistad, Gary B., Nomura, Daniel K., Casida, John E.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 06-10-2003; Elsevier
• Subjects: Animals; Arachidonic Acid - chemistry; Arachidonic Acid - pharmacology; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fatty Acids - antagonists & inhibitors; Fatty Acids - metabolism; Hydrolases - antagonists & inhibitors; Hydrolases - metabolism; Medical sciences; Mice; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Rats; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; CB1 cannabinoid receptor; Agonist; Sulfonamide; Rat; Enzyme; Arachidonic acid derivatives; Rodentia; Amidase; Central nervous system; Enzyme inhibitor; In vitro; Phosphorus Organic compounds; Biological activity; Sulfonyl halide; Vertebrata; Mammalia; Mouse; All cis stereoisomer; Animal; Hydrolases; Chemical synthesis; Brain (vertebrata)
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/S0960-894X(03)00721-2

Arachidonylsulfonyl fluoride (
3), reported here for the first time, is similar in potency to its known methyl arachidonylfluorophosphonate (
2) analogue as an inhibitor of mouse brain fatty acid amide hydrolase activity (IC
50 0.1 nM) and cannabinoid CB1 agonist [
3H]CP 55,940 binding (IC
50 304–530 nM). Interestingly,
3 is much more selective than
2 as an inhibitor for fatty acid amide hydrolase relative to acetylcholinesterase, butyrylcholinesterase and neuropathy target esterase.
N-(2-Hydroxyethyl)arachidonylsulfonamide (
4) is at least 2500-fold less potent than
N-(2-hydroxyethyl)arachidonamide (anandamide) (
1) at the CB1 agonist site.
Arachidonylsulfonyl fluoride (
3) inhibits mouse brain fatty acid amide hydrolase and a CB1 agonist site with IC
50 values of 0.11 and 304 nM, respectively. The corresponding
N-(2-hydroxyethyl) sulfonamide (
4) is at least 2500-fold less active than its analogue anandamide (
1) at the CB1 agonist site.