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New dopamine- and serotonin receptor subtypes, targets for antipsychotics drugs in vivo?
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maintain sufficient 5HT2/D2 receptor occupancy for therapeutic benefit in schizophrenic patients. 'Seroquel' is a trademark, the property of ZENECA Limited.
VI.A.4 THE RECEPTOR BINDING PROFILE OF MDL 100,907 P.L.M. v a n Giersbergen, B.M. B a r o n x, J. Elands, M.P. J o h n s o n I a n d S.M. Sorensen Hoechst Marion Roussek 16 rue d'Ankara, 67080 Strasbourg Cedex, France 12110 E. Galbraith Road, Cincinnati, 0H45215, U.S.A.
MDL 100 907 is a novel 5HT2A receptor antagonist in clinical development for schizophrenia. In this study, the binding profile of MDL 100 907 was determined. The affinity (Ki) of MDL 100907 for the 5HT2A receptor varied between 0.6 and 1.5 nM depending on the tissue used. Its affÉnities for the 5HT2c, ct1 and D 2 receptor were 63, 127 and 2264 nM, respectively. MDL 100907 was at least 100-fold less potent on any of the other 24 receptors tested than on the 5HTzA receptor. To determine the selectivity of MDL 100907 in vivo, EEDQ (N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline), an agent that irreversibly inactivates monoaminergic receptors, was used. Maximal protection of the 5HT2A receptor against alkylation was observed with MDL 100907 at doses as low as 0.3 mg/kg i.p. Lower doses were less effective. In contrast, at a dose of l0 mg/kg i.p., MDL 100907 was not able to protect the cq or the D2 receptor from alkylation with EEDQ. The present results demonstrate that MDL 100 907 in vitro and in vivo is a potent and highly selective 5HT2A receptor antagonist.
VI.A.5 NEW DOPAMINE- A N D SEROTONIN RECEPTOR SUBTYPES, TARGETS FOR ANTIPSYCHOTICS DRUGS IN VIVO? J.E. Leysen, W. Gommeren, P.M.F. Janssen and A. Schotte Department of Biochemical Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium
In recent years new subtypes of dopamine receptors (D3, D4, Ds) and serotonin receptors (5HTs, 5HT6, 5HT7) have been discovered by gene cloning. Various antipsychotic drugs were found to bind with high affinity to certain of these recombinant receptors in vitro, in particular D3-, D4- , 5HT 6- and 5HT 7receptors, prompting hypotheses on a possible role in antipsychotic drug action. Until now, only D3-receptors could, appa-
rently specifically, be detected by autoradiographic techniques in brain sections following incubation with a radioligand in particular conditions. We investigated the binding affinity of various antipsychotics for the recombinant dopamine- and serotonin receptor subtypes in vitro. We further attempted to detect D4- and 5HT7-receptors in brain sections of various mammalian species, including man, using radioligand binding in particular conditions and autoradiographic techniques. Only when reliable techniques are available to detect the receptor binding sites in brain tissue, occupancy of the receptors by drugs administered to animals can be investigated. Such techniques and selective agents will be required in order to provide more reliable indications for a possible role of the new receptor subtypes in antipsychotic drug action. Until then, all hypotheses remain highly speculative.
VI.A.6 THE PHARMACOLOGIC PROPERTIES OF 'SEROQUEL' (ICI 204,636) ARE CLOZAPINELIKE IN NEW TESTS FOR ATYPICAL ANTIPSYCHOTIC ACTIONS J.M. Goldstein Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19850 U.S.A.
'Seroquel' is a dibenzothiazepine antipsychotic agent in clinical development. The profile of 'Seroquel' is clozapine-like in terms of predicting low propensity to produce extrapyramidal side effects (EPS) and tardive dyskinesia (TD), eg, broad receptor profile with higher 5-HT2 relative to D2 binding, limbic selectivity, minimal dystonic liability in primate, transient prolactin elevations. Recently, new research findings have further established 'Seroquel' as an atypical antipsychotic agent: (1) 'Seroquel' fully substitutes for clozapine in a monkey drug discrimination paradigm; (2) 'Seroquel' restores prepulse inhibition disrupted by apomorphine in rats; (3) 'Seroquel' selectively increases Fos-like immunoreactivity in limbic but not motor related structures; (4) 'Seroquel' restores monkey social behavior that has been disrupted by amphetamine; (5) 'Seroquel' prolongs hindlimb retraction time over forelimb retraction time in the rat Paw Test. On the basis of the above results, 'Seroquel' exhibits pharmacological properties that distinguish it as an atypical antipsychotic agent with respect to minimal EPS and TD liability. The results in the monkey amphetamine social isolation paradigm suggest that 'Seroquel' may also be effective in treating the negative symptoms of schizophrenia. 'Seroquel' is a trademark, the property of ZENECA Limited.
maintain sufficient 5HT2/D2 receptor occupancy for therapeutic benefit in schizophrenic patients. 'Seroquel' is a trademark, the property of ZENECA Limited.
VI.A.4 THE RECEPTOR BINDING PROFILE OF MDL 100,907 P.L.M. v a n Giersbergen, B.M. B a r o n x, J. Elands, M.P. J o h n s o n I a n d S.M. Sorensen Hoechst Marion Roussek 16 rue d'Ankara, 67080 Strasbourg Cedex, France 12110 E. Galbraith Road, Cincinnati, 0H45215, U.S.A.
MDL 100 907 is a novel 5HT2A receptor antagonist in clinical development for schizophrenia. In this study, the binding profile of MDL 100 907 was determined. The affinity (Ki) of MDL 100907 for the 5HT2A receptor varied between 0.6 and 1.5 nM depending on the tissue used. Its affÉnities for the 5HT2c, ct1 and D 2 receptor were 63, 127 and 2264 nM, respectively. MDL 100907 was at least 100-fold less potent on any of the other 24 receptors tested than on the 5HTzA receptor. To determine the selectivity of MDL 100907 in vivo, EEDQ (N-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline), an agent that irreversibly inactivates monoaminergic receptors, was used. Maximal protection of the 5HT2A receptor against alkylation was observed with MDL 100907 at doses as low as 0.3 mg/kg i.p. Lower doses were less effective. In contrast, at a dose of l0 mg/kg i.p., MDL 100907 was not able to protect the cq or the D2 receptor from alkylation with EEDQ. The present results demonstrate that MDL 100 907 in vitro and in vivo is a potent and highly selective 5HT2A receptor antagonist.
VI.A.5 NEW DOPAMINE- A N D SEROTONIN RECEPTOR SUBTYPES, TARGETS FOR ANTIPSYCHOTICS DRUGS IN VIVO? J.E. Leysen, W. Gommeren, P.M.F. Janssen and A. Schotte Department of Biochemical Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium
In recent years new subtypes of dopamine receptors (D3, D4, Ds) and serotonin receptors (5HTs, 5HT6, 5HT7) have been discovered by gene cloning. Various antipsychotic drugs were found to bind with high affinity to certain of these recombinant receptors in vitro, in particular D3-, D4- , 5HT 6- and 5HT 7receptors, prompting hypotheses on a possible role in antipsychotic drug action. Until now, only D3-receptors could, appa-
rently specifically, be detected by autoradiographic techniques in brain sections following incubation with a radioligand in particular conditions. We investigated the binding affinity of various antipsychotics for the recombinant dopamine- and serotonin receptor subtypes in vitro. We further attempted to detect D4- and 5HT7-receptors in brain sections of various mammalian species, including man, using radioligand binding in particular conditions and autoradiographic techniques. Only when reliable techniques are available to detect the receptor binding sites in brain tissue, occupancy of the receptors by drugs administered to animals can be investigated. Such techniques and selective agents will be required in order to provide more reliable indications for a possible role of the new receptor subtypes in antipsychotic drug action. Until then, all hypotheses remain highly speculative.
VI.A.6 THE PHARMACOLOGIC PROPERTIES OF 'SEROQUEL' (ICI 204,636) ARE CLOZAPINELIKE IN NEW TESTS FOR ATYPICAL ANTIPSYCHOTIC ACTIONS J.M. Goldstein Zeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, Delaware 19850 U.S.A.
'Seroquel' is a dibenzothiazepine antipsychotic agent in clinical development. The profile of 'Seroquel' is clozapine-like in terms of predicting low propensity to produce extrapyramidal side effects (EPS) and tardive dyskinesia (TD), eg, broad receptor profile with higher 5-HT2 relative to D2 binding, limbic selectivity, minimal dystonic liability in primate, transient prolactin elevations. Recently, new research findings have further established 'Seroquel' as an atypical antipsychotic agent: (1) 'Seroquel' fully substitutes for clozapine in a monkey drug discrimination paradigm; (2) 'Seroquel' restores prepulse inhibition disrupted by apomorphine in rats; (3) 'Seroquel' selectively increases Fos-like immunoreactivity in limbic but not motor related structures; (4) 'Seroquel' restores monkey social behavior that has been disrupted by amphetamine; (5) 'Seroquel' prolongs hindlimb retraction time over forelimb retraction time in the rat Paw Test. On the basis of the above results, 'Seroquel' exhibits pharmacological properties that distinguish it as an atypical antipsychotic agent with respect to minimal EPS and TD liability. The results in the monkey amphetamine social isolation paradigm suggest that 'Seroquel' may also be effective in treating the negative symptoms of schizophrenia. 'Seroquel' is a trademark, the property of ZENECA Limited.