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 inverse agonist, 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 (CBD), a naturally occurring cannabinoid and a non-competitive CB₁/CB₂ receptor antagonist, as well as Δ⁹-tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid, modulate the effects of THC via direct blockade of cannabinoid CB₁ receptors, thus behaving like first-generation CB₁ receptor inverse agonists, such as rimonabant. CBD is a very low-affinity CB₁ ligand, that can nevertheless affect CB₁ receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB₁ receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB₁ receptor antagonism. THCV has also high affinity for CB₂ receptors and signals as a partial agonist, differing from both CBD and rimonabant.

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 CB₁ receptor antagonist / inverse agonist was rimonabant, discovered in 1994.

The endogenous cannabinoid system includes cannabinoid receptors, their endogenous ligands (endocannabinoids) and enzymes for their synthesis and degradation.

There are two main receptor types associated with the endocannabinoid signaling system: cannabinoid receptor 1 (CB₁) and 2 (CB₂). Both receptors are 7-transmembrane G-protein coupled receptors (GPCRs) which inhibit the accumulation of cyclic adenosine monophosphate within cells. CB₁ receptors are present in highest concentration in the brain but can also be found in the periphery. CB₂ receptors are mostly located in the immune and haematopoietic systems.

Endocannabinoids are eicosanoids acting as agonists for cannabinoid receptors, and they occur naturally in the body. Cannabinoid receptor-related processes are, for example, involved in cognition; memory; anxiety; control of appetite; emesis; motor behavior; sensory, autonomic, neuroendocrine, and immune responses; and inflammatory effects. There are two well-characterized endocannabinoids located in the brain and periphery. The first identified was anandamide (arachidonoyl ethanolamide), and the second was 2-AG (2-arachidonoyl glycerol). Additional endocannabinoids include virodhamine (O-arachidonoyl ethanolamine), noladin ether (2-arachidonoyl glyceryl ether) and NADA (N-arachidonoyl dopamine).

CB₁ receptors are coupled through G_i/o proteins and inhibit adenylyl cyclase and activate mitogen-activated protein (MAP) kinase. In addition, CB₁ receptors inhibit presynaptic N- and P/Q-type calcium channels and activate inwardly rectifying potassium channels. CB₁ antagonists produce inverse cannabimimetic effects that are opposite in direction from those produced by agonists for these receptors.

CB₁ receptors are highly expressed in hypothalamic areas which are involved in central food intake control and feeding behavior. This strongly indicates that the cannabinoid system is directly involved in feeding regulation. These regions are also interconnected with the mesolimbic dopamine pathway, the so-called "reward" system. Therefore, CB₁ antagonists might indirectly inhibit the dopamine-mediated rewarding properties of food. Peripheral CB₁ receptors are located in the gastrointestinal (GI) tract, liver and in adipose tissue. In the GI, CB₁ receptors are located on nerve terminals in the intestines. Endocannabinoids act at the CB₁ receptors to increase hunger and promote feeding and it is speculated that they decrease intestinal peristalsis and gastric emptying. Thus, antagonism at these receptors can inverse these effects. Also, in peripheral tissues, antagonism of CB₁ receptors increases insulin sensitivity and oxidation of fatty acids in muscles and the liver. A hypothetical scheme for the metabolic effects of CB₁ receptor antagonists is shown in Figure 1.

The first approach to develop cannabinoid antagonists in the late 1980s was to modify the structure of THC, but the results were disappointing. In the early 1990s new family of cannabinoid agonists was discovered from the NSAID (non-steroidal anti-inflammatory) drug pravadoline which led to the discovery of aminoalkyl indole antagonists with some but limited success. As the search based on the structure of agonists was disappointing it was no surprise that the first potent and selective cannabinoid antagonist belonged to an entirely new chemical family. In 1994 the first selective cannabinoid antagonist, SR141716 (rimonabant), was introduced by Sanofi belonging to a family of 1,5-diarylpyrazoles.