KT185

KT185 is an orally bioavailable inhibitor of α/β-hydrolase domain-containing protein 6 (ABHD6) with an IC₅₀ value of 0.21 nM in a competitive activity-based protein profiling assay using Neuro2A membranes.¹ It inhibits ABHD6 in a 2-arachidonoyl glycerol hydrolysis assay (IC₅₀ = 13.6 nM for the mouse recombinant enzyme expressed in HEK293T cells). KT185 is selective for ABHD6 over diacylglycerol lipase β (DAGLβ) at 1 ?M but inhibits lysophospholipase 1 (LYPLA1) and LYPLA2 at 10 ?M. It inhibits ABHD6 activity in mouse liver and brain in vivo when administered at doses of 5-10 and approximately 40 mg/kg, respectively, without inhibiting fatty acid amide hydrolase (FAAH) in the brain. KT185 inhibits increases in the frequency of spontaneous inhibitory post-synaptic currents (sIPSCs) induced by nicotine in the rat ventral tegmental area (VTA) but does not reduce nicotine self-administration in rats when administered intracerebroventricularly at a dose of 200 ?g.² It has been used as a negative control for the off-target effect of the DAGL inhibitor KT172 on ABHD6.

1.Hsu, K.L., Tsuboi, K., Chang, J.W., et al.Discovery and optimization of piperidyl-1,2,3-triazole ureas as potent, selective, and in vivo-active inhibitors of α/β-hydrolase domain containing 6 (ABHD6)J. Med. Chem.56(21)8270-8279(2013) 2.Buczynski, M.W., Herman, M.A., Hsu, K.L., et al.Diacylglycerol lipase disinhibits VTA dopamine neurons during chronic nicotine exposureProc. Natl. Acad. Sci. USA113(4)1086-1091(2016)