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Your search keyword '"S., DI SERIO"' showing total 2 results
Start Over Author "S., DI SERIO" Topic amidohydrolases
2 results on '"S., DI SERIO"'

1. Discovery of potent inhibitors of human and mouse fatty acid amide hydrolases.

Author

Butini S, Brindisi M, Gemma S, Minetti P, Cabri W, Gallo G, Vincenti S, Talamonti E, Borsini F, Caprioli A, Stasi MA, Di Serio S, Ros S, Borrelli G, Maramai S, Fezza F, Campiani G, and Maccarrone M

Subjects
Amidohydrolases chemistry, Analgesics chemistry, Analgesics pharmacology, Animals, Brain enzymology, CHO Cells, Cricetinae, Cricetulus, Cyclohexanes chemical synthesis, Cyclohexanes chemistry, Cyclohexanes pharmacology, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels antagonists & inhibitors, Furans chemical synthesis, Furans chemistry, Furans pharmacology, Humans, Hyperalgesia physiopathology, Maze Learning drug effects, Mice, Models, Molecular, Pain Threshold, Pyrroles chemical synthesis, Pyrroles chemistry, Pyrroles pharmacology, Rats, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins chemistry, Stereotyped Behavior drug effects, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Thiophenes pharmacology, Amidohydrolases antagonists & inhibitors, Analgesics chemical synthesis
Abstract

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.

Published
2012
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2. The novel reversible fatty acid amide hydrolase inhibitor ST4070 increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models.

Author

Caprioli A, Coccurello R, Rapino C, Di Serio S, Di Tommaso M, Vertechy M, Vacca V, Battista N, Pavone F, Maccarrone M, and Borsini F

Subjects
Acute Pain drug therapy, Acute Pain metabolism, Amidohydrolases metabolism, Animals, Arachidonic Acids metabolism, Glycerides metabolism, Male, Mice, Mice, Inbred NOD, Neuralgia metabolism, Polyunsaturated Alkamides metabolism, Rats, Rats, Sprague-Dawley, Amidohydrolases antagonists & inhibitors, Analgesics pharmacology, Brain drug effects, Brain metabolism, Endocannabinoids metabolism, Neuralgia drug therapy
Abstract

The effect of the enol carbamate 1-biphenyl-4-ylethenyl piperidine-1-carboxylate (ST4070), a novel reversible inhibitor of fatty acid amide hydrolase (FAAH), was investigated for acute pain sensitivity and neuropathic pain in rats and mice. Brain enzymatic activity of FAAH and the endogenous levels of its substrates, anandamide (AEA; N-arachidonoylethanolamine), 2-arachidonoylglycerol (2-AG), and N-palmitoylethanolamine (PEA), were measured in control and ST4070-treated mice. ST4070 (10, 30, and 100 mg/kg) was orally administered to assess mechanical nociceptive thresholds and allodynia by using the Randall-Selitto and von Frey tests, respectively. Neuropathy was induced in rats by either the chemotherapeutic agent vincristine or streptozotocin-induced diabetes, whereas the chronic constriction injury (CCI) model was chosen to evaluate neuropathy in mice. ST4070 produced a significant increase of nociceptive threshold in rats and counteracted the decrease of nociceptive threshold in the three distinct models of neuropathic pain. In diabetic mice, ST4070 inhibited FAAH activity and increased the brain levels of AEA and PEA, without affecting that of 2-AG. The administration of ST4070 generated long-lasting pain relief compared with pregabalin and the FAAH inhibitors 1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane (OL135) and cyclohexylcarbamic acid 3'-carbamoylbiphenyl-3-ylester (URB597) in CCI neuropathic mice. The antiallodynic effects of ST4070 were prevented by pretreatment with cannabinoid type 1 and cannabinoid type 2 receptor antagonists and by the selective peroxisome proliferator-activated receptor α antagonist [(2S)-2-[[(1Z)-1-methyl-3-oxo-3-[4-(trifluoromethyl)phenyl]-1-propenyl]amino]-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-carbamic acid ethyl ester (GW6471). The administration of ST4070 generated long-lasting neuropathic pain relief compared with pregabalin and the FAAH inhibitors OL135 and URB597. Taken together, the reversible FAAH inhibitor ST4070 seems to be a promising novel therapeutic agent for the management of neuropathic pain.

Published
2012
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