CONSTITUTIVELY ACTIVE 5-HYDROXYTRYPTAMINE(2C) RECEPTORS REVEAL NOVEL INVERSE AGONIST ACTIVITY OF RECEPTOR LIGANDS

5-HT2C receptor antagonists, such as mianserin and mesulergine, exhibi t negative intrinsic activity, defined as a decrease in agonist-indepe ndent, receptor mediated, phosphoinositide hydrolysis in cells transfe cted with the 5-HT2C receptor cDNA These drugs are classified as inver se agonists. Guanine nucleotides reciprocally modulate the binding of an agonist and inverse agonist, suggesting that an inverse agonist bin ds preferentially to the G protein uncoupled form of the 5-HT2C recept or. Another 5 HT2C receptor antagonist, 2-bromolysergic acid diethylam ide, 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 neut ral antagonist, causes 5-HT2C receptor down-regulation, suggesting tha t the biological effects of 5-HT2C receptor antagonists are not solely due to antagonism of endogenous agonist. These results provide eviden ce that constitutively active 5-HT2C receptors are biologically signif icant. The functionally distinct properties of inverse agonists and ne utral antagonists may elucidate the mechanisms controlling basal recep tor activity states and lead to novel approaches in the development of therapeutic agents.