Endocannabinoid-Based Therapies

Abstract

The endocannabinoids are lipid-derived messengers that play a diversity of regulatory roles in mammalian physiology. Dysfunctions in their activity have been implicated in various disease conditions, attracting attention to the endocannabinoid system as a possible source of therapeutic drugs. This signaling complex has three components: the endogenous ligands, anandamide and 2-arachidonoyl- sn-glycerol (2-AG); a set of enzymes and transporters that generate, eliminate, or modify such ligands; and selective cell surface receptors that mediate their biological actions. We provide an overview of endocannabinoid formation, deactivation, and biotransformation and outline the properties and therapeutic potential of pharmacological agents that interfere with those processes. We describe small-molecule inhibitors that target endocannabinoid-producing enzymes, carrier proteins that transport the endocannabinoids into cells, and intracellular endocannabinoid-metabolizing enzymes. We briefly discuss selected agents that simultaneously interfere with components of the endocannabinoid system and with other functionally related signaling pathways. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

“…The mutants constitutively lack NAAA mRNA, protein, and enzyme activity (Supplementary Fig. 8), and do not compensate for this absence with altered transcription of isofunctional enzymes (fatty acid amide hydrolase) (Piomelli & Mabou Tagne, 2022), PEA-producing enzymes ( N -acyl-phosphatidylethanolamine phospholipase D) (Okamoto et al , 2004) or other lysosomal lipid hydrolases (acid ceramidase and ß-glucocerebrosidase) (Park & Schuchman, 2006; Do et al , 2019) (Supplementary Fig. 8).…”

Adolescent Exposure to Low-Dose THC Disrupts Energy Balance and Adipose Organ Homeostasis in Adulthood

“…S3G, H). Transcription of N-acylphosphatidyl-ethanolamine phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH) -which produce and deactivate, respectively, anandamide and other non-cannabinoid lipid amides (Lu and Mackie, 2016;Piomelli and Mabou Tagne, 2022) -was increased in WAT, but not in BAT (Supplemental Fig. S3E, F).…”

“…The endogenous cannabinoid system (ECS) is found in most, if not all, mammalian organs and is involved in a diversity of physiological processes (Lu and Mackie, 2016;Piomelli and Mabou Tagne, 2022). It is comprised of two G protein-coupled receptors (CB1 and CB2), two lipid-derived ligands [anandamide and 2-arachidonoyl-sn-glycerol (2-AG)], and various enzymes and transporter proteins responsible for the formation, transmembrane transfer, and degradation of such ligands (Lu and Mackie, 2016;Piomelli and Mabou Tagne, 2022).…”

“…The endogenous cannabinoid system (ECS) is found in most, if not all, mammalian organs and is involved in a diversity of physiological processes (Lu and Mackie, 2016;Piomelli and Mabou Tagne, 2022). It is comprised of two G protein-coupled receptors (CB1 and CB2), two lipid-derived ligands [anandamide and 2-arachidonoyl-sn-glycerol (2-AG)], and various enzymes and transporter proteins responsible for the formation, transmembrane transfer, and degradation of such ligands (Lu and Mackie, 2016;Piomelli and Mabou Tagne, 2022). All constituents of the ECS are represented in white and brown adipose tissues -the parenchymal components of the adipose organ (Cinti, 2018) -where endocannabinoid substances may act as 'thrifty' autocrine/paracrine messengers (DiPatrizio and Piomelli, 2012;Piazza et al, 2017) to enhance lipogenesis and attenuate non-shivering thermogenesis (Mazier et al, 2015;Ruiz de Azua and Lutz, 2019;Jung et al, 2022).…”

The Synthetic Cannabinoid URB447 Exerts Antitumor and Antimetastatic Effect in Melanoma and Colon Cancer

“…ECS receptors are widespread throughout the body and involved in different physiological processes. It is the omnipresence what makes CB receptors a potential target for several pathologies [ 5 , 6 ]. In fact, CB receptors are expressed in a wide variety of cancers with different origin, such as glioma and melanoma, to name a few [ 7 , 8 ].…”