Cannabinoid Receptor Antagonist - Mechanism of Action

Mechanism of Action

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.