Cannabinoid Receptor G Protein-Coupling and Inverse Agonism

G protein-coupled CB1 cannabinoid receptors are found in high density in the nervous system. CB1 cannabinoid receptors have the ability to change conformation between inactive and active receptor states in the absence of agonists. The ability to adopt an active conformation in the absence of agonists results in constitutive receptor signaling. Inverse agonists reverse the constitutive activity of the receptor in the absence of agonists also antagonize receptor activity due to the presence of agonists. This dual effect of the CB1 cannabinoid receptor inverse agonist SR141716A is a result of its ability to bind both inactive and active receptors, but with a relatively higher affinity for the inactive receptor. The higher affinity of SR141716A for the inactive receptor is due to its ability to hydrogen bond to lysine 3.28 in transmembrane helix 3, a residue available to SR141716A only in the inactive state.