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In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2017 Nov 15; Vol. 815, pp. 42-48. Date of Electronic Publication: 2017 Oct 07. - Publication Year :
- 2017
-
Abstract
- Although exogenous agonists for cannabinoid (CB) receptors are clinically effective for treating chronic pain, global activation of brain CB receptors causes frequent central nervous system (CNS) side-effects. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide (AEA), an endogenous CB. Recently, we discovered a novel FAAH inhibitor, 3-pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477). In vitro studies demonstrated that ASP8477 inhibited human FAAH-1, FAAH-1 (P129T) and FAAH-2 activity with IC <subscript>50</subscript> values of 3.99, 1.65 and 57.3nM, respectively. ASP8477 at 10µM had no appreciable interactions with 65 different kinds of receptors, ion channels, transporters and enzymes, including CB <subscript>1</subscript> and CB <subscript>2</subscript> receptors and monoacylglycerol lipase. In adolescent rats, orally administered ASP8477 (0.3-10mg/kg) elevated AEA concentrations in both plasma and brain. In a capsaicin-induced secondary hyperalgesia model, a pretreatment with ASP8477 significantly improved mechanical allodynia and thermal hyperalgesia at 0.3-3mg/kg p.o. ASP8477 also significantly improved mechanical allodynia in an L5/L6 spinal nerve ligation neuropathic pain model, with an ED <subscript>50</subscript> value of 0.63mg/kg, and in a streptozotocin-induced diabetic neuropathy model at 3 and 10mg/kg p.o. Furthermore, ASP8477 significantly attenuated the reduction in rearing events at 1 and 3mg/kg p.o. in a monoiodoacetic acid-induced osteoarthritis model. Importantly, ASP8477 had no significant effect on motor coordination up to 30mg/kg p.o. These results indicate that ASP8477 is a potent, selective, and oral active FAAH inhibitor with activity in the CNS, with the potential to be a new analgesic agent with a wide safety margin.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Subjects :
- Administration, Oral
Analgesics administration & dosage
Analgesics pharmacology
Animals
Arachidonic Acids metabolism
Carboxylic Acids administration & dosage
Dose-Response Relationship, Drug
Endocannabinoids metabolism
Enzyme Inhibitors administration & dosage
Humans
Male
Polyunsaturated Alkamides metabolism
Psychomotor Performance drug effects
Rats
Amidohydrolases antagonists & inhibitors
Carboxylic Acids pharmacology
Enzyme Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 815
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 29017758
- Full Text :
- https://doi.org/10.1016/j.ejphar.2017.10.007