کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5554329 1558865 2017 7 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor
موضوعات مرتبط
علوم زیستی و بیوفناوری علم عصب شناسی علوم اعصاب سلولی و مولکولی
پیش نمایش صفحه اول مقاله
In vitro and in vivo pharmacological characterization of ASP8477: A novel highly selective fatty acid amide hydrolase inhibitor
چکیده انگلیسی

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 IC50 values of 3.99, 1.65 and 57.3 nM, respectively. ASP8477 at 10 µM had no appreciable interactions with 65 different kinds of receptors, ion channels, transporters and enzymes, including CB1 and CB2 receptors and monoacylglycerol lipase. In adolescent rats, orally administered ASP8477 (0.3-10 mg/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 0.3-3 mg/kg p.o. ASP8477 also significantly improved mechanical allodynia in an L5/L6 spinal nerve ligation neuropathic pain model, with an ED50 value of 0.63 mg/kg, and in a streptozotocin-induced diabetic neuropathy model at 3 and 10 mg/kg p.o. Furthermore, ASP8477 significantly attenuated the reduction in rearing events at 1 and 3 mg/kg p.o. in a monoiodoacetic acid-induced osteoarthritis model. Importantly, ASP8477 had no significant effect on motor coordination up to 30 mg/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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Pharmacology - Volume 815, 15 November 2017, Pages 42-48
نویسندگان
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