RECEPTOR-BINDING PROPERTIES INVITRO AND INVIVO OF RITANSERIN - A VERY POTENT AND LONG-ACTING SEROTONIN-S-2 ANTAGONIST

  • 1 January 1985
    • journal article
    • research article
    • Vol. 27  (6) , 600-611
Abstract
In vitro and in vivo receptor-binding properties of the new serotonin antagonist, ritanserin, are reported. In in vitro binding assays, ritanserin shows high affinity binding to serotonin-S2 sites in rat frontal cortex tissue: IC50 = 0.9 nM without drug preincubation and 0.3 nM with 30-min drug preincubation; IC50 values for histamine-H1, dopamine-D2, and adrenergic-.alpha.1 and -.alpha.2 sites were 39-, 77-, 107-, and 166-fold higher and at up to 1 .mu.M, the drug did not bind to serotonin-S1 sites. In in vitro assays, ritanserin dissociated very slowly from serotonin-S2 (t1/2 = 160 min) and histamine-H1 sites (t1/2 = 77 min) and rapidly from dopamine-D2 sites (t1/2 = 11 min). Half-times of dissociation from adrenergic-.alpha.1 and -.alpha.2 sites were 18 and 26 min. The inhibition by ritanserin of [3H]ketanserin binding was found to be partially noncompetitive and the inhibitory potency increased with drug preincubation. Due to the slow dissociation of ritanserin from the serotonin-S2 sites, the drug cannot be displaced completely by [3H]ketanserin. In contrast, inhibition by ritanserin of [3H]haloperidol binding to dopamine-D2 sites in rat striatum was fully competitive, in agreement with the rapid dissociation of the drug from the latter sites. In ex vivo binding assays using brain areas of rats and guinea pigs treated s.c. with ritanserin, occupation of serotonin-S2 sites was observed at very low dose (50% occupation at 0.08-0.1 mg/kg) and sites remained occupied during a prolonged time period (> 70% occupation up to 48 h after 2.5 mg/kg ritanserin). Histamine-H1 receptor sites in guinea pig cerebellum became occupied at dosages 25-fold higher than the dosage producing occupation of frontal cortical serotonin-S2 sites. Dopamine-D2 sites in rat striatum and cortical adrenergic-.alpha.1 sites became only slightly occupied (< 20%) at higher dosages and the effect was not dose-dependent. Adrenergic-.alpha.2 sites were not occupied up to doses of 160 mg/kg given s.c. In vivo binding assays using [3H]spiperone confirmed the occupation of frontal cortical serotonin-S2 sites following lobe dosage of ritanserin and a minor occupation of striatal dopamine-D2 sites. Levels of dopamine and serotonin and their metabolites remained unchanged in brains areas of rats orally treated with ritanserin up to dosages of 40 mg/kg. At 160 mg/kg, there seemed to be a slight reduction in dopamine and serotonin content. These observations indicated that serotonin turnover was not affected by serotonin-S2 receptor blockade. The study showed that in vitro and in vivo interactions of ritanserin with serotonin-S2 and histamine-H1 sites were in good agreement. However, in the in vitro binding to dopamine-D2 and .alpha.-adrenergic sites was not evident under in vivo conditions. The discrepancies between in vitro and in vivo binding data demonstrate that, for evaluating the activity profile of drugs, both approaches of investigation are necessary. Ritanserin appeared to be a relatively selective, extremely potent, long rating, and centrally active serotonin-S2 antagonist. The drug probably represents a useful tool for investigating the role of serotonin-S2 sites in brain disorders.