Druggable Targets in Endocannabinoid Signaling
Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC
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Druggable Targets in Endocannabinoid Signaling Ann M. Gregus and Matthew W. Buczynski
Abstract
Keywords
Cannabis and cannabinoid-based extracts have long been utilized for their perceived therapeutic value, and support for the legalization of cannabis for medicinal purposes continues to increase worldwide. Since the discovery of Δ9-tetrahydrocannabinol (THC) as the primary psychoactive component of cannabis over 50 years ago, substantial effort has been directed toward detection of endogenous mediators of cannabinoid activity. The discovery of anandamide and 2- arachidonoylglycerol as two endogenous lipid mediators of cannabinoid-like effects (endocannabinoids) has inspired exponential growth in our understanding of this essential pathway, as well as the pathological conditions that result from dysregulated endocannabinoid signaling. This review examines current knowledge of the endocannabinoid system including metabolic enzymes involved in biosynthesis and degradation and their receptors, and evaluates potential druggable targets for therapeutic intervention.
Endocannabinoid · GPCR · CB1 · CB2 · FAAH
A. M. Gregus · M. W. Buczynski (*) School of Neuroscience, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA e-mail: [email protected]
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Cannabinoids as Therapeutics
For centuries, cannabis and cannabinoid-based extracts were thought to possess therapeutic value. In recent years, the use of medical marijuana has increased for a wide variety of disorders in the United States, and changes in the legal landscape and public opinion support expanding its recreational availability nationwide. The 2010, a resolution adopted by the American Medical Association advocated reconsideration of marijuana as a Schedule I controlled substance given the potential therapeutic value of marijuana and cannabis-based products. As of January 1, 2020, 33 states have legalized the sale of medical marijuana, with additional states considering similar legislation with possible enaction in the near future. The primary psychoactive component of cannabis was identified as Δ9-tetrahydrocannabinol (THC) by Yechiel Gaoni and Raphael Mechoulam in the 1960s [1, 2]. While hundreds of bioactive molecules have been identified in cannabis thus far [3], THC recapitulates many of the pharmacological properties attributed to marijuana in both rodent models and in humans [4, 5]. Subsequent
© Springer Nature Switzerland AG 2020 Y. Kihara (ed.), Druggable Lipid Signaling Pathways, Advances in Experimental Medicine and Biology 1274, https://doi.org/10.1007/978-3-030-50621-6_8
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worldwide efforts were aimed at the discovery of both synthetic and semi-synthetic cannabinoids capable of producing cannabinoid-like effects in vivo for the eventual development of patentable drugs with verifiable therapeutic value. While many hundreds of cannabinoid compounds were created in subsequent years, the pharmacological properties of these compounds often retained or exacerbated psychoactive effects when
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