Flumezapine, an antagonist of central dopamine and serotonin receptors

Flumezapine, 7-fluoro-2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3- b] [1,5]benzodiazepine, antagonized the increases in serum corticosterone concentration caused by a serotonin agonist, quipazine, and by a dopamine agonist, pergolide, in rats. Flumezapine did not alter the elevation of serum corticosterone by a kappa opioid agonist, bremazocine. Flumezapine resembled but was more potent than clozapine and zotepine in blocking these effects of quipazine and pergolide, differing from spiperone and fluphenazine which were selective antagonists of pergolide and from metergoline and mianserin which were selective antagonists of quipazine. All of the antagonists had high affinity for 5HT2 receptors as measured by radioligand-binding in vitro. Spiperone, fluphenazine, zotepine and flumezapine had high affinity for dopamine D2 receptors as measured by radioligand-binding in vitro. The potency of the compounds in antagonizing the pergolide-induced elevation of serum corticosterone concentration matched their affinity for D2 receptors in vitro. There was poor correlation between the potency of the compounds in antagonizing the quipazine-induced elevation of serum corticosterone concentration and their affinity for 5HT2 receptors in vitro, possibly indicating that the receptor mediating the effect of quipazine is not identical to or exclusively the 5HT2 receptor. The results suggest that flumezapine is a potent blocker of dopamine D2 and of some serotonin receptors.