Pharmacological profile of ritanserin: A very specific central serotonin S2-antagonist

Ritanserin, a novel methylenepiperidine derivative, was studied in a wide range of common pharmacological tests mainly in rats. The lowest ED50, 0.0070 mg/kg, was obtained against tryptamine‐induced cyanosis. At 0.037 mg/kg, tryptamine‐induced bilateral clonic seizures were inhibited. Slightly higher doses, up to 0.11 mg/kg, inhibited mescaline and 5‐hydroxytryptophan (5‐HTP)‐induced head twitches and antagonized tryptamine‐induced coarse body tremors. Ritanserin did not generalize with LSD but was a weak antagonist of the LSD‐discriminative stimulus. Potent serotonin S2‐antagonism was confirmed by the inhibition of reactions mediated by endogenous serotonin, such as reversal of mast cell serotonin (5‐HT) cyanosis (0.012 mg/kg) and inhibition of gastric lesions (0.028 mg/kg). The lowest dose reducing the intensity of serotonin‐induced skin reactions was 0.04 mg/kg. Reduction of histamine‐induced skin reactions required a dose of at least 10 mg/kg. Time‐course studies in several tests indicated a relatively long duration of serotonin S2‐antagonism. Ritanserin doses up to 40 mg/kg were devoid of central dopamine antagonism and did not interfere with the neurotransmitters norepinephrine and acetylcholine. In an additional series of interactions and functional tests, ritanserin was virtually devoid of effect. In the wide range of tests, peripheral histamine antagonism was the first activity component unrelated to serotonin and it was observed at 270 times the dose for central S2‐antagonism. It is concluded that ritanserin is a very effective central serotonin S2‐antagonist which is at the same time relatively long acting and very specific.