Constitutively active 5-hydroxytryptamine2C receptors reveal novel inverse agonist activity of receptor ligands.

5-HT2C receptor antagonists, such as mianserin and mesulergine, exhibit negative intrinsic activity, defined as a decrease in agonist-independent, receptor-mediated, phosphoinositide hydrolysis in cells transfected with the 5-HT2C receptor cDNA. These drugs are classified as inverse agonists. Guanine nucleotides reciprocally modulate the binding of an agonist and inverse agonist, suggesting that an inverse agonist binds preferentially to the G protein-uncoupled form of the 5-HT2C receptor. Another 5-HT2C receptor antagonist, 2-bromolysergic acid diethylamide, functions as a neutral antagonist with no intrinsic activity, but is able to block both agonist and inverse agonist. Chronic treatment of choroid plexus cells with an inverse agonist, but not with the neutral antagonist, causes 5-HT2C receptor down-regulation, suggesting that the biological effects of 5-HT2C receptor antagonists are not solely due to antagonism of endogenous agonist. These results provide evidence that constitutively active 5-HT2C receptors are biologically significant. The functionally distinct properties of inverse agonists and neutral antagonists may elucidate the mechanisms controlling basal receptor activity states and lead to novel approaches in the development of therapeutic agents.