Discovery of Potent Inhibitors of Human and Mouse Fatty Acid Amide Hydrolases
| Autor: | Filomena Fezza, Stefania Butini, Giuseppe Borrelli, Stefano Di Serio, Silvia Vincenti, Antonio Caprioli, Samuele Maramai, Giuseppe Campiani, Mauro Maccarrone, Grazia Gallo, Margherita Brindisi, Sandra Gemma, Walter Cabri, Emanuela Talamonti, Sindu Ros, Franco Borsini, Patrizia Minetti, Maria Antonietta Stasi |
|---|---|
| Přispěvatelé: | Butini S, Brindisi M, Gemma S, Minetti P, Cabri W, Gallo G, Vincenti S, Talamonti E, Borsin F, Caprioli A, Stasi MA, Di Serio S, Ros S, Borrelli G, Maramai S, Fezza F, Campiani G, Maccarrone M, Butini, Stefania, Brindisi, Margherita, Gemma, Sandra, Patrizia, Minetti, Walter, Cabri, Grazia, Gallo, Silvia, Vincenti, Emanuela, Talamonti, Franco, Borsini, Antonio, Caprioli, maria antonietta, Stasi, stefano di, Serio, Sindu, Ro, Borrelli, Giuseppe, Maramai, Samuele, Filomena, Fezza, Campiani, Giuseppe, Mauro, Maccarrone |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Pain Threshold ERG1 Potassium Channel Cannabinoid receptor medicine.drug_class hERG CHO Cells Thiophenes Anxiolytic Amidohydrolases chemistry.chemical_compound Mice Structure-Activity Relationship Cricetulus Fatty acid amide hydrolase Cyclohexanes Cricetinae Drug Discovery medicine Animals Humans Pyrroles Settore BIO/10 Furans Maze Learning chemistry.chemical_classification Analgesics Fatty acid amide biology Fatty acid Brain faah Endocannabinoid system Ether-A-Go-Go Potassium Channels Recombinant Proteins Rats Enzyme nervous system chemistry Biochemistry Hyperalgesia biology.protein Molecular Medicine lipids (amino acids peptides and proteins) Stereotyped Behavior psychological phenomena and processes |
| Popis: | Fatty acid amide hydrolase (FAAH, EC 3.5.1.99) is the main enzyme catabolizing endocannabinoid fatty acid amides. FAAH inactivation promotes beneficial effects upon pain and anxiety without the side effects accompanying agonists of type-1 cannabinoid receptors. Aiming at discovering new selective FAAH inhibitors, we developed a series of compounds (5a-u) characterized by a functionalized heteroaromatic scaffold. Particularly, 5c and 5d were identified as extremely potent, noncompetitive, and reversible FAAH inhibitors endowed with a remarkable selectivity profile and lacking interaction with the hERG channels. In vivo antinociceptive activity was demonstrated for 5c, 5d, and 5n at a dose much lower than that able to induce either striatal and limbic stereotypies or anxiolytic activity, thus outlining their potential to turn into optimum preclinical candidates. Aiming at improving pharmacokinetic properties and metabolic stability of 5d, we developed a subset of nanomolar dialyzable FAAH inhibitors (5v-z), functionalized by specific polyethereal lateral chains and fluorinated aromatic rings. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|