Ritanserin, a novel methylenepiperidine derivative, acts as a potent, long-lasting, and specific central serotonin S2 antagonist in rats. It inhibits tryptamine-induced cyanosis at 0.0070 mg/kg and bilateral clonic seizures at 0.037 mg/kg, and it blocks mescaline- and 5-HTP-induced head twitches at doses up to 0.11 mg/kg. The compound does not generalize with LSD but weakly antagonizes the LSD discriminative stimulus. It reverses mast cell serotonin cyanosis at 0.012 mg/kg and inhibits gastric lesions at 0.028 mg/kg. Ritanserin shows no central dopamine antagonism or interference with norepinephrine or acetylcholine at doses up to 40 mg/kg. Peripheral histamine antagonism requires 270 times the central S2-antagonism dose.
An intravenous dose of 20.0 mg/kg of mescaline reliably caused head-twitching in rats. Many drugs with different pharmacological actions were tested for their ability to block this response, including numerous serotonin antagonists and two selective S2 antagonists: ketanserin and pirenperone. The same compounds were also examined in six in vivo tests measuring antagonism at serotonin, dopamine, norepinephrine, histamine, or acetylcholine sites. Inhibition of mescaline-induced head-twitches did not correlate with blocking dopamine, norepinephrine, histamine, or acetylcholine receptors, but did correlate with in vivo antagonism of tryptamine and 5-hydroxytryptophan, and with inhibition of 3H-spiperone binding to rat prefrontal cortex in...