Cannabinoid receptor antagonist

A cannabinoid receptor antagonist, also known simply as a cannabinoid antagonist or as an anticannabinoid, is a type of cannabinoidergic drug that binds to cannabinoid receptors (CBR) and prevents their activation by endocannabinoids. They include antagonists, inverse agonists, and antibodies of CBRs. The discovery of the endocannabinoid system led to the development of CB₁ receptor antagonists. The first CBR antagonist, rimonabant, was described in 1994. Rimonabant blocks the CB₁ receptor selectively and has been shown to decrease food intake and regulate body-weight gain. The prevalence of obesity worldwide is increasing dramatically and has a great impact on public health. The lack of efficient and well-tolerated drugs to cure obesity has led to an increased interest in research and development of CBR antagonists.Cannabidiol, a naturally occurring cannabinoid, is a non-competitive CB₁/CB₂ receptor antagonist.

For centuries hashish and marijuana from the Indian hemp Cannabis sativa L. have been used for medicinal and recreational purposes. In 1840, Schlesinger S. was apparently the first investigator to obtain an active extract from the leaves and flowers of hemp. A few years later, in 1848, Decourtive E. described the preparation of an ethanol extract that on evaporation of the solvent gave a dark resin, which he named “cannabin”. In 1964 the main active constituent of C. sativa L., Δ⁹-tetrahydrocannabinol (THC), was isolated and synthesized by Mechoulam's laboratory. Two types of cannabinoid receptors, CB₁ and CB₂, responsible for the effects of THC were discovered and cloned in the early 1990s. Once cannabinoid receptors had been discovered, it became important to establish whether their agonists occur naturally in the body. This search led to the discovery of the first endogenous cannabinoid (endocannabinoid), anandamide (arachidonoyl ethanolamide). Later on other endocannabinoids were found, for example 2-AG (2-arachidonoyl glycerol). These findings raised further questions about the pharmacological and physiological role of the cannabinoid system. This revived the research on cannabinoid receptor antagonists which were expected to help answer these questions. The use of the cannabinoid agonist, THC, in its many preparations to enhance appetite is a well known fact. This fact led to the logical extension that blocking of the cannabinoid receptors might be useful in decreasing appetite and food intake. It was then discovered that the blockage of the CB₁ receptor represented a new pharmacological target. The first specific CB₁receptor antagonist / inverse agonist was rimonabant, discovered in 1994.

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