AbstractThe endocannabinoid system is a unique neuromodulatory system that affects a wide range of biological processes and maintains the homeostasis in all mammal body systems. In recent years, several pharmacological tools to target endocannabinoid neurotransmission have been developed, including direct and indirect cannabinoid agonists and cannabinoid antagonists. Due to their hydrophobic nature, cannabinoid agonists and antagonists need to bind specific transporters to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key determinant of drug pharmacokinetics. As HSA binds both the endocannabinoid anandamide and the active ingredient of Cannabis sativa, Δ‐9‐tetrahydrocannabinol, we hypothesize that HSA can be the most important carrier of cannabinoid drugs. In silico docking observations strongly indicate that HSA avidly binds the indirect cannabinoid agonists URB597, AM5206, JZL184, JZL195, and AM404, the direct cannabinoid agonists WIN55,212-2 and CP55,940, and the prototypical cannabinoid antagonist/inverse agonist SR141716. Values of the free energy for cannabinoid drugs binding to HSA range between −5.4 kcal mol–1 and −10.9 kcal mol–1. Accounting for the HSA concentration in vivo (∼ 7.5 × 10–4 M), values of the free energy here determined suggest that the formation of the HSA:cannabinoid drug complexes may occur in vivo. Therefore, HSA appears to be an important determinant for cannabinoid efficacy and may guide the choice of the drug dose regimen to optimize drug efficacy and to avoid drug‐related toxicity. © 2017 IUBMB Life, 69(11):834–840, 2017.

01 Sep 2017·Journal of Molecular NeuroscienceQ3 · MEDICINE

Inhibitor of Endocannabinoid Deactivation Protects Against In Vitro and In Vivo Neurotoxic Effects of Paraoxon

Q3 · MEDICINE

Article

Author: Romine, Heather ; McEwan, Sara A ; Farizatto, Karen L G ; Karanian, David A ; Almeida, Michael F ; Shukla, Vidyanand G ; Nikas, Spyros P ; Byrd, Aaron ; Makriyannis, Alexandros ; Naidoo, Vinogran ; Bahr, Ben A

The anticholinesterase paraoxon (Pxn) is related to military nerve agents that increase acetylcholine levels, trigger seizures, and cause excitotoxic damage in the brain. In rat hippocampal slice cultures, high-dose Pxn was applied resulting in a presynaptic vulnerability evidenced by a 64% reduction in synapsin IIb (syn IIb) levels, whereas the postsynaptic protein GluR1 was unchanged. Other signs of Pxn-induced cytotoxicity include the oxidative stress-related production of stable 4-hydroxynonenal (4-HNE)-protein adducts. Next, the Pxn toxicity was tested for protective effects by the fatty acid amide hydrolase (FAAH) inhibitor AM5206, a compound linked to enhanced repair signaling through the endocannabinoid pathway. The Pxn-mediated declines in syn IIb and synaptophysin were prevented by AM5206 in the slice cultures. To test if the protective results in the slice model translate to an in vivo model, AM5206 was injected i.p. into rats, followed immediately by subcutaneous Pxn administration. The toxin caused a pathogenic cascade initiated by seizure events, leading to presynaptic marker decline and oxidative changes in the hippocampus and frontal cortex. AM5206 exhibited protective effects including the reduction of seizure severity by 86%, and improving balance and coordination measured 24 h post-insult. As observed in hippocampal slices, the FAAH inhibitor also prevented the Pxn-induced loss of syn IIb in vivo. In addition, the AM5206 compound reduced the 4-HNE modifications of proteins and the β1 integrin activation events both in vitro and in vivo. These results indicate that Pxn exposure produces oxidative and synaptic toxicity that leads to the behavioral deficits manifested by the neurotoxin. In contrast, the presence of FAAH inhibitor AM5206 offsets the pathogenic cascade elicited by the Pxn anticholinesterase.

01 Apr 2013·The AAPS JournalQ3 · MEDICINE

The Interaction of Fatty Acid Amide Hydrolase (FAAH) Inhibitors with an Anandamide Carrier Protein Using 19 F-NMR

Q3 · MEDICINE

Article

Author: Zhuang, Jianqin ; Nikas, Spyros P. ; Zhao, Jianhong ; Makriyannis, Alexandros ; Yang, De-Ping ; Guo, Jianxin

It has been reported that the endocannabinoid anandamide (AEA) binds to a class of fatty acid-binding proteins and serum albumin which can serve as carrier proteins and potentiate the cellular uptake of AEA and its intracellular translocation. Here, we employed (19)F nuclear magnetic resonance spectroscopy to study the interactions of serum albumin with two inhibitors of fatty acid amide hydrolase (FAAH), the enzyme involved in the deactivation of anandamide. We found that, for both inhibitors AM5206 and AM5207, the primary binding site on serum albumin is drug site 1 located at subdomain IIA. Neither inhibitor binds to drug site 2. While AM5207 binds exclusively to drug site 1, AM5206 also interacts with other fatty acid-binding sites on serum albumin. Additionally, AM5206 has an affinity for serum albumin approximately one order of magnitude higher than that of AM5207. The data suggest that interactions of FAAH inhibitors with albumin may provide added advantages for their ability to modulate endocannabinoid levels for a range of applications including analgesia, antiemesis, and neuroprotection.

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Indication	Highest Phase	Country/Location	Organization	Date
Neurodegenerative Diseases	Preclinical	US	The University of North Carolina at Pembroke	11 Nov 2010
Neurodegenerative Diseases	Preclinical	US	MAKScientific LLC	11 Nov 2010
Seizures	Preclinical	US	The University of North Carolina at Pembroke	11 Nov 2010
Seizures	Preclinical	US	MAKScientific LLC	11 Nov 2010

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