Discovery and Development of Endocannabinoid-Hydrolyzing Enzyme Inhibitors

Abstract

Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) are hydrolytic enzymes which degrade the endogenous cannabinoids (endocannabinoids) N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), respectively. Endocannabinoids are an important class of lipid messenger molecules that are produced on demand in response to elevated intracellular calcium levels. They recognize and activate the cannabinoid CB(1) and CB(2) receptors, the molecular targets for Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in marijuana evoking several beneficial therapeutic effects. However, in vivo the cannabimimetic effects of AEA and 2-AG remain weak owing to their rapid inactivation by FAAH and MGL, respectively. The inactivation of FAAH and MGL by specific enzyme inhibitors increases the levels of AEA and 2-AG, respectively, producing therapeutic effects such as pain relief and depression of anxiety.

Chemical Probes of Endocannabinoid Metabolism

“…More recently, pharmacological agents were developed that potently and selectively block MAGL activity and elevate 2-AG levels in vivo, enabling, for the first time, direct comparison between the enhanced actions of each endocannabinoid. Multiple recent reviews have described the generation of endocannabinoid hydrolase inhibitors in detail (Minkkilä et al, 2010;Petrosino and Di Marzo, 2010;Otrubova et al, 2011;Feledziak et al, 2012). Here, we will focus our discussion on inhibitors that have been most widely used to probe endocannabinoid function in vivo.…”

“…Selective pharmacological tools to disrupt the activity of MAGL in vivo have only become available within the last few years, but already they have been used to demonstrate the role of this enzyme in 2-AG signaling termination and the potential translational use of targeting MAGL in the treatment of nervous system disorders such as pain, anxiety, drug addiction, nausea, and neuroinflammation (Minkkilä et al, 2010;Petrosino and Di Marzo, 2010;Nomura et al, 2011b).…”

“…In 2009, we reported a selective and in vivo-active MAGL inhibitor, JZL184 (Fig. 5B) , which has been used to demonstrate MAGL's role in 2-AG signaling termination and the potential translational use of targeting MAGL in the treatment of nervous system disorders such as pain, anxiety, drug addiction, and nausea (Minkkilä et al, 2010;Petrosino and Di Marzo, 2010). JZL184 is a piperidine carbamate that was shown to inhibit MAGL through irreversible carbamoylation of the enzyme's catalytic serine (Long et al, 2009b) and is another prime example of the carbamate reactive group as a privileged scaffold for serine hydrolase inhibitor design.…”

N-(2-Oxo-3-oxetanyl)carbamic Acid Esters as N-Acylethanolamine Acid Amidase Inhibitors: Synthesis and Structure–Activity and Structure–Property Relationships

“…37 The compound was prepared by means of a two-step procedure reported in the literature: 36 Synthesis of Cyclobutylcarbamic Acid Benzyl Ester (13). 38 To a stirred solution of NaHCO 3 Synthesis of (R,S)-2-Oxocyclobutylcarbamic Acid Benzyl Ester (15). 36 The compound was prepared following a literature procedure: 36 Synthesis of (S)-1-Methyl-3-(2-oxo-3-oxetanyl)urea (19a).…”

Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids

“…The identification of the enzymes involved in the degradation of endocannabinoids prompted a search for inhibitory compounds that target these enzymes [43]. AEA is mainly degraded by fatty acid amide hydrolase (FAAH) [44], whereas 2-AG is primarily metabolized by monoacylglycerol lipase (MAGL) [45].…”