Blinded prospective evaluation of computer-based mechanistic schizophrenia disease model for predicting drug response
3区 · 综合性期刊
作者: Geerts, Hugo ; Spiros, Athan ; Roberts, Patrick ; Twyman, Roy ; Alphs, Larry ; Grace, Anthony A.
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.
2002-07-01·Psychopharmacology3区 · 医学
Stimulation by antipsychotic agents of mitogen-activated protein kinase (MAPK) coupled to cloned, human (h)serotonin (5-HT)(1A) receptors.
3区 · 医学
作者: Didier Cussac ; Delphine Duqueyroix ; Adrian Newman-Tancredi ; Mark J Millan
There is evidence that serotonergic mechanisms contribute to the functional profiles of antipsychotic drugs, several of which display affinity for human (h)5-HT(1A) receptors.
Here, we compared the interaction of several antipsychotic agents at h5-HT(1A) receptors employing mitogen-activated protein kinase (MAPK), an intracellular marker.
The influence of antipsychotics on MAPK phosphorylation was quantified in Chinese hamster ovary (CHO) cells stably transfected with h5-HT(1A) receptors by use of a highly selective antibody.
The novel antipsychotic agent, S16924, concentration-dependently (pEC(50), 8.10) stimulated the phosphorylation of MAPK. Its maximal effect (96%) was similar to that of the prototypical 5-HT(1A) agonist, (+)8-OH-DPAT (pEC(50), 8.54) (defined as 100%). The selective 5-HT(1A) receptor antagonist WAY100,635, which was inactive alone, abolished stimulation of MAPK by S16924 with a pK(b) of 9.66. This stimulatory influence of S16924 on MAPK was potently mimicked by the benzoisoxazole, antipsychotic ziprasidone (pEC(50), 7.25; 93%). The atypical antipsychotic clozapine also activated MAPK, albeit with lower potency and efficacy (pEC(50), 5.43 and 43%). These actions of ziprasidone and clozapine were also blocked by WAY100,635. Evaluated at a single, high concentration, several other antipsychotics stimulated MAPK phosphorylation with variable efficacy: quetiapine (75%), ocaperidone (74%), tiospirone (57%), olanzapine (54%) and risperidone (21%). In all cases, their actions were abolished by WAY100,635. In contrast, haloperidol, thioridazine and sertindole did not stimulate MAPK.
Antipsychotics display contrasting efficacies in modulating MAPK phosphorylation at h5-HT(1A) receptors, ranging from high (e.g. S16924 and ziprasidone), via intermediate (e.g. clozapine) to low (e.g. haloperidol). Differential modulation of 5-HT(1A) receptor-coupled MAPK may contribute to their contrasting functional profiles.
2001-12-14·European Journal of Pharmacology3区 · 医学
Agonist, antagonist, and inverse agonist properties of antipsychotics at human recombinant 5-HT1A receptors expressed in HeLa cells
3区 · 医学
作者: Cosi, Cristina ; Koek, Wouter
Agonist and antagonist properties of antipsychotics at human (h) recombinant 5-hydroxytryptamine (h5-HT(1A)) receptor have been examined previously in transfected Chinese hamster ovary (CHO) cells using 5'-O-(3-[(35)S]thio)-triphosphate ([(35)S] GTP gamma S) binding. Na(+)-dependent [35S] GTP gamma S binding to membranes from human epithelioid carcinoma (HeLa) cells, expressing 500 fmol/mg protein of h5-HT(1A) receptor (HA7 cells), appears suitable to characterize not only agonist and antagonist properties of 5-HT(1A) receptor ligands, but also inverse agonist properties. We therefore examined agonist, antagonist, and inverse agonist activity of antipsychotics at h5-HT(1A) receptor in HA7 cells. Some antipsychotics had agonist activity and stimulated [(35)S] GTP gamma S binding with the following order of efficacy: nemonapride>ziprasidone>clozapine>ocaperidone. Tiospirone and trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7,5]-oxepino-[4,5c]pyrrole (ORG 5222), were more potent h5-HT(1A) receptor antagonists than raclopride, olanzapine, and risperidone. Haloperidol, chlorpromazine, thioridazine, pimozide, and sertindole showed Na(+)-dependent inverse agonist activity at h5-HT(1A) receptor that could be antagonized by (s)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide [(s)-WAY 100135]. These results are further evidence that interactions with h5-HT(1A) receptors could play a role in the pharmacological profile of certain antipsychotics, and that Na(+) affects the ability to detect inverse agonist activity at h5-HT(1A) receptors, likely by influencing receptor precoupling. Also, the manner in which compounds interact with 5-HT(1A) receptors appears to be related to their K(b)/K(i) ratio.