AM 1172

AM 1172 is a potent and selective inhibitor of stable anandamide uptake with IC50 of 2.1 - 2.5 μM and fatty acid amide hydrolase (FAAH) with Ki of 3.18 μM.

FAAH, a member of serine hydrolase enzyme family, is an integral membrane hydrolase that hydrolyzes bioactive amides, including anandamide, to free fatty acid and ethanolamine. In vitro, FAAH displays esterase and amidase activity. In vivo, this protein acts as the principal catabolic enzyme for a class of bioactive lipids called the fatty acid amides (FAAs).

AM1172 blocked [3H] anandamide internalization in rodent cortical neurons and human astrocytoma cells but not acted as an inhibitor of FAAH 1. In mouse cortical neurons, This component also blocked the uptake of tritiated AEA with an EC50 of about 1.5 µM 1.

Regarding the effect of AM 1172 administration in vivo, the evidence should be provided by performing the study in human or mice or other animal models.

Reference:
1.  Fegley D, Kathuria S, Mercier R, et al. Anandamide transport is independent of fatty-acid amide hydrolase activity and is blocked by the hydrolysis-resistant inhibitor AM1172. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(23):8756-8761.

Arvanil, olvanil, AM 1172 and LY 2183240 (various cannabinoid CB1 receptor agonists) increase the threshold for maximal electroshock-induced seizures in mice.[Pubmed:29335158]

Pharmacol Rep. 2018 Feb;70(1):106-109.

BACKGROUND: Recent evidence reveals therapeutic potential for cannabinoids to reduce seizure frequency, severity and duration. Animal models are useful tools to determine the potential antiseizure or antiepileptic effects of cannabinoids. The objective of this study was evaluation of the effect of arvanil, olvanil, AM 1172 and LY 2183240, the compounds interacted with endocannabinoid and/or endovanilloid systems, on convulsions in the commonly used model of convulsions in mice. METHODS: Arvanil and olvanil were injected intraperitoneally (ip) 30min and AM 1172 and LY 2183240 were administered ip 60min before the maximal electroshock seizure threshold (MEST) test. The criterion for convulsant activity was tonic hindlimb extension. RESULTS: Arvanil, olvanil, AM 1172 and LY 2183240 dose-dependently increased the electroconvulsive threshold in mice. The TID20 (threshold increasing dose 20) values for arvanil, olvanil, AM 1172 and LY 2183240 were 0.9, 2.18, 2.48 and 3.56mgkg(-1), respectively, and the TID50 (threshold increasing dose 50) values were 1.88, 6.45, 6.29 and 10.04mgkg(-1), respectively. CONCLUSION: This study identified anticonvulsant effects of arvanil, olvanil, AM 1172 and LY 2183240. The order of the magnitude of the anticonvulsant effects of the examined compounds was following: arvanil>olvanil>AM 1172>LY 2183240.

Studies of anandamide accumulation inhibitors in cerebellar granule neurons: comparison to inhibition of fatty acid amide hydrolase.[Pubmed:17901541]

J Mol Neurosci. 2007 Sep;33(1):18-24.

The endocannabinoid, N-arachidonylethanolamine (AEA) is accumulated by neurons via a process that has been characterized biochemically but not molecularly. Inhibitors of AEA accumulation have been characterized individually but have not been compared in a single study. Our purpose was to compare the potency of five previously described compounds (AM404, AM1172, VDM11, OMDM-2, and UCM707) both as inhibitors of AEA and N-palmitoylethanolamine (PEA) accumulation by cerebellar granule neurons and as inhibitors of AEA hydrolysis. The compounds all inhibited AEA accumulation; AM404, VDM11 and OMDM-2 with IC(50) values of approximately 5 microM, whereas AM1172 and UCM707 exhibited IC(50) values of 24 and 30 microM, respectively. The compounds also inhibited PEA accumulation; AM404 being the most potent with an IC(50) of 6 microM, whereas the other compounds had IC(50) values in the range of 30-70 microM. All of the compounds potently inhibited AEA hydrolysis by brain membranes; the K(I) values for AM404, VDM11, and UCM707 were less than 1 microM; AM1172 and OMDM-2 exhibited K(I) values of 3 and 10 microM, respectively. The IC(50) values for inhibition of AEA accumulation were compared to the IC(50) values for PEA accumulation and AEA hydrolysis using linear regression. None of the regressions were significant. These data indicate that inhibition of AEA accumulation by neurons is not a result of the inhibition of endocannabinoid hydrolysis and is a process different from the accumulation of PEA. These studies support the hypothesis that the cellular AEA accumulation beyond simple equilibrium between intracellular and extracellular concentrations occurs because AEA binds to an intracellular protein that is not FAAH but that also recognizes the AEA uptake inhibitors.

Anandamide uptake is consistent with rate-limited diffusion and is regulated by the degree of its hydrolysis by fatty acid amide hydrolase.[Pubmed:16461355]

J Biol Chem. 2006 Apr 7;281(14):9066-75.

The uptake of arachidonoyl ethanolamide (anandamide, AEA) in rat basophilic leukemia cells (RBL-2H3) has been proposed to occur via a saturable transporter that is blocked by specific inhibitors. Measuring uptake at 25 s, when fatty acid amide hydrolase (FAAH) does not appreciably affect uptake, AEA accumulated via a nonsaturable mechanism at 37 degrees C. Interestingly, saturation was observed when uptake was plotted using unbound AEA at 37 degrees C. Such apparent saturation can be explained by rate-limited delivery of AEA through an unstirred water layer surrounding the cells (1). In support of this, we observed kinetics consistent with rate-limited diffusion at 0 degrees C. Novel transport inhibitors have been synthesized that are either weak FAAH inhibitors or do not inhibit FAAH in vitro (e.g. UCM707, OMDM2, and AM1172). In the current study, none of these purported AEA transporter inhibitors affected uptake at 25 s. Longer incubation times illuminate downstream events that drive AEA uptake. Unlike the situation at 25 s, the efficacy of these inhibitors was unmasked at 5 min with appreciable inhibition of AEA accumulation correlating with partial inhibition of AEA hydrolysis. The uptake and hydrolysis profiles observed with UCM707, VDM11, OMDM2, and AM1172 mirrored two selective and potent FAAH inhibitors CAY10400 and URB597 (at low concentrations), indicating that weak inhibition of FAAH can have a pronounced effect upon AEA uptake. At 5 min, the putative transport inhibitors did not reduce AEA uptake in FAAH chemical knock-out cells. This strongly suggests that the target of UCM707, VDM11, OMDM2, and AM1172 is not a transporter at the plasma membrane but rather FAAH, or an uncharacterized intracellular component that delivers AEA to FAAH. This system is therefore unique among neuro/immune modulators because AEA, an uncharged hydrophobic molecule, diffuses into cells and partial inhibition of FAAH has a pronounced effect upon its uptake.