INVITRO AND INVIVO RECEPTOR-BINDING AND EFFECTS ON MONOAMINE TURNOVERIN RAT-BRAIN REGIONS OF THE NOVEL ANTIPSYCHOTICS RISPERIDONE AND OCAPERIDONE

Risperidone and ocaperidone are new benzisoxazol antipsychotics with p articularly beneficial effects in schizophrenia. We report a comprehen sive study on the in vitro and in vivo receptor binding profile of the new compounds, compared with haloperidol, and on the drug effects on monoamine and metabolite levels in various brain areas. The in vitro r eceptor binding and monoamine uptake inhibition profiles, comprising 2 9 receptors and four monoamine uptake systems, revealed that ocaperido ne and risperidone bound primarily, and with the highest affinity thus far reported, to serotonin 5HT2 receptors (K(i) values of 0.14 and 0. 12 nm, respectively). Further, the drugs bound at nanomolar concentrat ions to the following receptors (K(i) values, in nM, for ocaperidone a nd risperidone, respectively): alpha(1)-adrenergic (0.46 and 0.81), do pamine D2 (0.75 and 3.0), histamine H-1 (1.6 and 2.1), and alpha(2)-ad renergic (5.4 and 7.3). In contrast, haloperidol showed nanomolar affi nity for D2 receptors (1.55) and haloperidol-sensitive sigma-sites (0. 84) only. The in vitro binding affinity of ocaperidone, risperidone, a nd haloperidol for D2 receptors was exactly the same when measured in membranes from rat striatum, nucleus accumbens, tuberculum olfactorium , and human kidney cells expressing the cloned human D2 receptor (long form). In vivo binding rats, using intravenous administration of [H-3 ]spiperone, revealed very potent occupation by ocaperidone and risperi done of 5HT2 receptors in the frontal cortex (ED50 of 0.04-0.03 mg/kg) ; in this respect, they were 6, 30, and 100 times more potent than rit anserin, haloperidol, and clozapine, respectively. Ocaperidone occupie d D2 receptors in the striatum and the nucleus accumbens with similar potency as did haloperidol (ED50 of 0.14-0.16 mg/kg). Risperidone reve aled biphasic inhibition curves in the latter brain areas, indicating that [H-3] spiperone labeled both 5HT2 receptors (occupied by risperid one at < 0.04 mg/kg) and D2 receptors (risperidone ED50 of approximate ly 1 mg/kg). In the tuberculum olfactorium, 5HT2 and D2 receptors were also distinguished with risperidone. The ED50 values for occupation o f the latter were for ocaperidone and risperidone 2 times lower and fo r haloperidol 2 times higher than in the striatum. Ocaperidone, risper idone, and haloperidol readily increased the levels of the dopamine me tabolites 3,4-dihydroxybenzene acetic acid and homovanillic acid in th e striatum, the nucleus accumbens, the tuberculum olfactorium, and, to some extent, the frontal cortex. Dose-response curve shapes were mark edly different; with ocaperidone maximal levels were reached at 0.16 m g/kg and maintained to 10 mg/kg); with risperidone the levels tended t o increase continuously up to 10 mg/kg. Haloperidol produced dome-shap ed curves (maximum at 0.16-0.63 mg/kg). The decline in dopamine metabo lite levels at high haloperidol doses was accompanied by a 50% reducti on in dopamine levels in the various brain areas. In contrast, ocaperi done and risperidone caused only 20% reduction of striatal dopamine le vels and did not affect dopamine levels in the mesolimbic areas. The l evels of the serotonin metabolite 5-hydroxyindole acetic acid remained exactly the same in all the brain areas with all three drugs. Hence, the feedback activation of monoamine turnover upon receptor blockade o bserved in the dopaminergic system appeared not to take place in the s erotonergic system. Our findings in vitro and in vivo show that risper idone and ocaperidone both have an equal, extremely high, affinity for brain 5HT2 receptors. Potent 5HT2 antagonism is hypothesized to under ly the therapeutic action of the drugs on negative symptoms in schizop hrenia. Central D2 receptor blockade is believed to have a major role in the effective treatment of positive symptoms of schizophrenia; in t his respect ocaperidone is equipotent with haloperidol, whereas risper idone is somewhat less potent. Extrapyramidal side effects are inheren t to central D2 receptor blockade, but the side-effects can be attenua ted by potent 5HT2 receptor blockade. The primary 5HT2 receptor affini ty of both risperidone and ocaperidone probably underlies their reduce d side-effect liability.