The range of available FAAH inhibitors far exceeded MAGL inhibitors, with most MAGL inhibitors lacking selectivity, highlighting a gap in the endocannabinoid pharmacology toolkit.
Read this if you're interested in the pharmaceutical chemistry behind drugs that modulate the endocannabinoid system.
FAAH inhibitors were extensive and selective; MAGL inhibitors were few and non-selective
What the researchers found
This review cataloged and compared all known synthetic inhibitors of FAAH and MAGL, the two primary enzymes that break down the endocannabinoids anandamide and 2-AG.
FAAH inhibitors fell into two groups: substrate-inspired compounds (mimicking the fatty acid chains of anandamide, oleamide, or PEA) and structurally novel compounds (carbamates, oxazolopyridines, imidazolidines, and even some NSAIDs). The substrate-inspired group was extensive and included highly selective compounds.
MAGL inhibitors were far fewer in number and most lacked selectivity, meaning they also inhibited other enzymes. This disparity reflected the earlier characterization of FAAH and the greater research attention it had received.
The review provided detailed comparisons of synthetic pathways, potencies, selectivities, and mechanisms of inhibition to facilitate research tool selection.
Why it matters
Selective enzyme inhibitors are essential tools for understanding endocannabinoid function and for developing therapeutics. This catalog highlighted the urgent need for better MAGL inhibitors, a gap that has since been addressed.
The numbers in context
FAAH inhibitor families: substrate-inspired (arachidonoyl, oleoyl, palmitoyl chains) and novel (carbamates, oxazolopyridines, etc.). MAGL inhibitors: few members, most lacking selectivity. FAAH was cloned nearly simultaneously with MAGL but received far more pharmacological attention.
How the study worked
Comprehensive review of published literature on FAAH and MAGL inhibitor chemistry, covering synthetic pathways, potencies (IC50 values), selectivities, and mechanisms of action for all known inhibitor families.
What this study cannot tell us
As a chemistry-focused review, it did not cover in vivo efficacy or safety in detail. The field was evolving rapidly, and new inhibitors were being developed. Some potency comparisons across studies using different assay conditions must be interpreted cautiously.
How to read the evidence
This is a comprehensive medicinal chemistry review providing a thorough catalog of the field's chemical tools, with moderate evidence quality for the comparisons made.
When this study was published
Published in 2008. Since then, highly selective MAGL inhibitors have been developed and some have entered clinical trials.
The bigger picture
This review influenced the direction of medicinal chemistry efforts in the endocannabinoid field. The identified gap in MAGL inhibitors was subsequently addressed, leading to selective MAGL inhibitors that are now in clinical trials.
Questions still open
- Can highly selective MAGL inhibitors be developed for clinical use? How do the therapeutic profiles of FAAH vs. MAGL inhibition differ?
Common questions
Why does it matter which enzyme is blocked?
Could these compounds become medicines?
Read the original research
Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.
Current topics in medicinal chemistry, 8(3), 247-67
Citation
Vandevoorde, Séverine. (2008). Overview of the chemical families of fatty acid amide hydrolase and monoacylglycerol lipase inhibitors.. Current topics in medicinal chemistry, 8(3), 247-67.
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