Biochemical profile of risperidone, a new antipsychotic.
Risperidone was compared to the 5-hydroxytryptamine2 antagonist ritanserin and to the dopamine-D2 antagonist haloperidol. The in vitro receptor binding (neurotransmitter-, peptide- and ion channel binding sites) and neurotransmitter uptake profile were investigated. Risperidone revealed, like ritanserin, a very high binding affinity for 5-hydroxytryptamine2 receptors (Ki = 0.16 and 0.30 nM, respectively) and a slow dissociation (half-time, 31 and 160 min). In accordance, risperidone (IC50 = 0.5 nM) and ritanserin (IC50 = 1.8 nM) potently blocked serotonin-induced 32P-phosphatidic acid formation in human blood platelets. Risperidone showed, like haloperidol, high binding affinity for dopamine-D2 receptors (Ki = 3.13 and 1.55 nM, respectively) and rapid dissociation (half-time, 2.7 and 5.8 min). Risperidone displayed higher binding affinity than ritanserin and haloperidol for alpha-1 adrenergic (Ki = 0.8 nM), histamine-H1 (Ki = 2.23 nM) and alpha-2 adrenergic receptors (Ki = 7.54 nM). In in vitro superfusion experiments, risperidone and haloperidol reversed at nanomolar concentrations the inhibition by LY 171555 (a dopamine-D2 agonist) and by amphetamine of potassium and electrically evoked release of [3H]acetylcholine from striatal slices (postsynaptic dopamine-D2 effects). Both drugs reversed with similar potency the inhibition by LY 171555 of electrically evoked release of [3H]dopamine (a presynaptic dopamine-D2 effect). Risperidone did not affect the activation by amphetamine of [3H]dopamine efflux from rat striatal slices. Risperidone enhanced at nanomolar concentrations the stimulated [3H]norepinephrine efflux from cortical slices and it similarly reversed the inhibition by clonidine, at concentrations corresponding to its binding affinity for alpha-2 adrenergic receptors. The in vitro biochemical properties of risperidone are in agreement with the reported in vivo pharmacological profile, the relation to clinical findings is discussed.
Leysen
J E
JE
Department of Biochemical Pharmacology and Biochemistry, Janssen Research Foundation, Beerse, Belgium.
Gommeren
W
W
Eens
A
A
de Chaffoy de Courcelles
D
D
Stoof
J C
JC
Janssen
P A
PA
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004873:Ergolines / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000493:pharmacokinetics; D007555:Isoxazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D008958:Models, Molecular; D009638:Norepinephrine / Q000378:metabolism; D010080:Oxazoles / Q000493:pharmacokinetics*; D010712:Phosphatidic Acids / Q000378:metabolism; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D019257:Quinpirole; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D018967:Risperidone; D016713:Ritanserin; D014961:X-Ray Diffraction
D014150:Antipsychotic Agents; D004873:Ergolines; D007555:Isoxazoles; D010080:Oxazoles; D010712:Phosphatidic Acids; D010880:Piperidines; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D016713:Ritanserin; D019257:Quinpirole; D006220:Haloperidol; D018967:Risperidone; D004298:Dopamine; D009638:Norepinephrine