piperidines and ocaperidone

The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA) and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2) antagonist and ocaperidone, a very high affinity dopamine D(2) antagonist, using only pharmacology and human positron emission tomography (PET) imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS) total score and the higher extra-pyramidal symptom (EPS) liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

Topics: Antipsychotic Agents; Computer Simulation; Humans; Models, Neurological; Neostriatum; Piperidines; Prospective Studies; Pyridazines; Pyrimidinones; Schizophrenia; Treatment Outcome

5-HT(1A) receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [3H]WAY100,635 ([3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT(1A) receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTPgammaS (100 microM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTPgammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTPgammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTPgammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTPgammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [35S]GTPgammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT(1A) receptors, was less influenced by GTPgammaS. When the ratio of high-/low-affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [3H]-WAY100,635 binding by GTPgammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT(1A) receptors. These may contribute to differing profiles of antipsychotic activity.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Chlorpromazine; CHO Cells; Clozapine; Cricetinae; Dose-Response Relationship, Drug; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Haloperidol; Humans; Membranes; Piperazines; Piperidines; Pyridines; Pyrimidinones; Pyrrolidines; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Thiazoles; Thioridazine; Tritium

The 5-hydroxytryptamine (5-HT) 1D/1B receptors have gained particular interest as potential targets for treatment of migraine and depression. G-protein coupling and other intrinsic properties of the human 5-HT(1D) receptor were studied using a baculovirus-based expression system in Sf9 cells. Coexpression of the human 5-HT(1D) receptor with Galpha(i1), alpha(i2), alpha(i3), or Galpha(o)-proteins and Gbeta(1)gamma(2)-subunits reconstituted a Gpp(NH)p-sensitive, high affinity binding of [(3)H]5-HT to this receptor, whereas the Galpha(q)beta(1)gamma(2) heterotrimer was ineffective in this respect. Competition of [(3)H]5-HT binding by various compounds confirmed that coexpression of the human 5-HT(1D) receptor with Galpha(i/o)beta(1)gamma(2) reconstitutes the receptor in a high affinity agonist binding state, having the same pharmacological profile as the receptor expressed in mammalian cells. Binding of the antagonist ocaperidone to the human 5-HT(1D) receptor in coupled or noncoupled state was analyzed. This compound competed with [(3)H]5-HT binding more potently on the human 5-HT(1D) receptor in the noncoupled state, showing its inverse agonistic character. Ocaperidone acted as a competitive inhibitor of [(3)H]5-HT binding when tested with the coupled receptor form but not so when tested with the noncoupled receptor preparation. Finally, [(35)S]GTPgammaS binding experiments using the inverse agonist ocaperidone revealed a high level of constitutive activity of the human 5-HT(1D) receptor. Taken together, the reconstitution of the human 5-HT(1D) receptor-G-protein coupling using baculovirus-infected Sf9 cells made possible the assessment of coupling specificity and the detection of different binding states of the receptor induced by G-protein coupling or ligand binding.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Cells, Cultured; GTP-Binding Proteins; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Insecta; Piperidines; Protein Conformation; Pyrimidinones; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Serotonin; Sulfur Radioisotopes; Tritium

Ocaperidone, a new benzisoxazolyl piperidine neuroleptic, was compared with haloperidol, risperidone and ritanserin in a large series of pharmacological tests. Ocaperidone inhibited dopamine agonist (apomorphine, amphetamine or cocaine)-induced behavioral effects at low doses (0.014-0.042 mg/kg) and was, thereby, equipotent with haloperidol (0.016-0.024 mg/kg) and 2.0 to 8.3 times more potent than risperidone. Ocaperidone completely blocked the dopamine agonist behavior at slightly higher doses (0.064 mg/kg) and was, thereby, more potent and efficacious than haloperidol (0.097-0.13 mg/kg) and risperidone (0.59-1.17 mg/kg). The dissociation between inhibition of apomorphine behavior and induction of catalepsy was as high for ocaperidone (22) as for risperidone (20) and higher than for haloperidol (8), suggesting risperidone-like low extrapyramidal side effect liability. Ocaperidone also antagonized serotonin agonist (tryptamine, mescaline or 5-hydroxytryptophan)-induced behavioral effects (0.011-0.064 mg/kg) and was, thereby, equipotent with risperidone (0.014-0.056 mg/kg) and at least as potent as ritanserin (0.037-0.13 mg/kg). Ocaperidone displayed its serotonin and dopamine antagonism at the same dose levels, in contrast to risperidone, which was a predominant serotonin antagonist. Apart from protection from compound 48/80 lethality (0.042 mg/kg) and norepinephrine lethality (0.097 mg/kg), which were not considered to hinder its clinical application, no additional secondary effects were observed at low doses of ocaperidone. In the apomorphine test in dogs, ocaperidone was very potent (i.v., s.c. and p.o. ED50 values: less than 1.0 micrograms/kg) and showed a rapid onset (less than 0.5 h) and long duration of action (24 h) after p.o. administration. Ocaperidone is concluded to be a highly potent and efficacious dopamine-D2 antagonist with concomitant, equivalent serotonin 5-HT2 antagonism. Ocaperidone is expected to exert pronounced haloperidol-like effects on the positive symptoms of schizophrenic patients but with risperidone-like low extrapyramidal side effect liability and improved patient compliance.

Topics: Animals; Antiemetics; Antipsychotic Agents; Apomorphine; Behavior, Animal; Body Temperature; Dogs; Dopamine Agents; Dopamine Antagonists; Eating; Female; Haloperidol; Isoxazoles; Lethal Dose 50; Locomotion; Male; Mice; Motor Activity; Muscles; Neurotransmitter Agents; Piperidines; Posture; Pyrimidinones; Rats; Rats, Inbred Strains; Risperidone; Ritanserin; Serotonin; Serotonin Antagonists; Synaptic Transmission

The mixed serotonin-2/dopamine-D2 antagonists risperidone and ocaperidone were compared with the specific D2 antagonist haloperidol for their ability to antagonize amphetamine (10 mg/kg, s.c.)-induced stereotypy in rats. Four successive stages of amphetamine antagonism were differentiated: 1) disinhibition: reversal of stationary stereotypy into the hyperactivity normally observed with lower doses of amphetamine; 2) inhibition: the first significant reduction of activity; 3) normalization: reduction of activity to the level of nonamphetaminized rats; and 4) suppression: reduction of activity to 50% of the level of nonamphetaminized rats. Ocaperidone and risperidone were equipotent with haloperidol for disinhibition (0.0062-0.011 mg/kg). However, the disinhibition was maintained over a wider dose range with risperidone (factor 84) than with haloperidol (9.0) and ocaperidone (4.1) and was also more pronounced in magnitude with risperidone. Ocaperidone was equipotent with haloperidol for inhibition (0.013-0.025 mg/kg) and normalization (0.074-0.080 mg/kg) but 4.4 times less potent for suppression of activity (0.71 vs. 0.16 mg/kg). Risperidone became progressively less potent than haloperidol: 4.4 times for inhibition, 9.6 times for normalization and 22 times for suppression of activity. The present data are consistent with the hypothesis that serotonin-2 antagonism compensates for the functional consequences of D2 receptor blockade. The implications for the clinical application of the compounds are discussed.

Topics: Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Haloperidol; Isoxazoles; Male; Motor Activity; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Risperidone

Risperidone and ocaperidone are new benzisoxazol antipsychotics with particularly beneficial effects in schizophrenia. We report a comprehensive 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 receptor binding and monoamine uptake inhibition profiles, comprising 29 receptors and four monoamine uptake systems, revealed that ocaperidone and risperidone bound primarily, and with the highest affinity thus far reported, to serotonin 5HT2 receptors (Ki values of 0.14 and 0.12 nM, respectively). Further, the drugs bound at nanomolar concentrations to the following receptors (Ki values, in nM, for ocaperidone and risperidone, respectively): alpha 1-adrenergic (0.46 and 0.81), dopamine D2 (0.75 and 3.0), histamine H1 (1.6 and 2.1), and alpha 2-adrenergic (5.4 and 7.3). In contrast, haloperidol showed nanomolar affinity for D2 receptors (1.55) and haloperidol-sensitive sigma sites (0.84) only. The in vitro binding affinity of ocaperidone, risperidone, and 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 in rats, using intravenous administration of [3H]spiperone, revealed very potent occupation by ocaperidone and risperidone 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 ritanserin, haloperidol, and clozapine, respectively. Ocaperidone occupied D2 receptors in the striatum and the nucleus accumbens with similar potency as did haloperidol (ED50 of 0.14-0.16 mg/kg). Risperidone revealed biphasic inhibition curves in the latter brain areas, indicating that [3H] spiperone labeled both 5HT2 receptors (occupied by risperidone at less than 0.04 mg/kg) and D2 receptors (risperidone ED50 of approximately 1 mg/kg). In the tuberculum olfactorium, 5HT2 and D2 receptors were also distinguished with risperidone. The ED50 values for occupation of the latter were for ocaperidone and risperidone 2 times lower and for haloperidol 2 times higher than in the striatum. Ocaperidone, risperidone, and haloperidol readily increased the levels of the dopamine metabolites 3,4-dihydroxybenzene acetic acid and homovanillic acid in the striatum, the nucleus accumbens, the tubercul

Topics: Animals; Antipsychotic Agents; Biogenic Monoamines; Brain; Female; Haloperidol; In Vitro Techniques; Isoxazoles; Male; Neurotransmitter Agents; Piperidines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Risperidone; Spiperone; Tissue Distribution