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Title: MedChem for Drug addiction: Targeting the endocannabinoid system

Abstract: The endocannabinoid system acts as neurotransmission mechanism modulating various brain functions, such as reward and drug use. This system, named after the herb Cannabis sativa and its chemical constituents (delta-9-tetrahydrocannabinol and others), comprises two cannabinoid receptors (CB1 and CB2), their endogenous ligands (endocannabinoids, anandamide and 2-arachidonoylglicerol) and the enzymes responsible for endocannabinoid metabolism. Various compounds have been developed to modulate endocannabinoid function in the brain, including inverse agonists, antagonists and agonists selectively binding CB1 or CB2 receptors, as well as endocannabinoid hydrolysis inhibitors. Preclinical pharmacological studies have revealed their applications and limitations as potential drugs to treat drug addiction. CB1 receptor inverse agonists exert robust effects in inhibiting behavioral changes induced by psychostimulant drugs, particularly cocaine. The clinical use of these compounds, however, are hampered by their propensity to induce side effects consisting of mood changes and anxiety. More recently, CB2 receptor agonists have also been investigated. They are efficacious in preventing cocaine effects with more favorable safety profiles as compared to CB1 antagonists. Other potential strategies to developing new treatments based on the endocannabinoid system may include CB1 receptor “neutral” antagonists and endocannabinoid hydrolysis inhibitors.

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