- Email: [email protected]
The preclinical profile of an original pyridobenzoxazepine, JL 13
P.3 Psychotic disorders and antipsychotics
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IP.3.030 I No evidence of association between dopamine 03 receptorgeneand bipolar disorder in a sardinian sample G. Severino, M.A. Palmas, S. Ruiu,M. Del Zompo, P.Piccardi. Department ofNeurosciences "B.B. Brodie", University of Cagliari, Cagliari, Italy The dopamine OJ receptor is a candidate gene for psychiatric disorders. There have been several positive and negative reports regarding a potential role of dopamineD3 receptorgene locus (DR03) in bipolaraffective disorders. Linkage studies ruled out a D3 gene involvement in bipolar disorder (Nanko et al, 1993). Likewise, negative results were foundby association studies comparing bipolar patients with controls about its role in genetic predisposition to bipolaraffective disorder. However. Parsian et aI. (1995) have recently reported an association between bipolar affective disorder and DRO) using the haplotyperelative risk (HRR) approach. The potentialrelevance of the latterfinding promptedus to studyDR03 alleles in a sampleof 44 nuclearSardinian families with bipolardisorder. Forty-four unrelated probands, 12 Bipolar 1, II Bipolar II and 21 Schizoaffective Bipolar, with both parents alive were recruited from the Center of ClinicalPsychopharmacology of Department of Neurosciences "B. B. Brodie", University of Cagliari. Admission to the study was independent on family history. All probands, their parents and affected sibs gave informedconsent to participate in the study and to have venous blood sample drawn. All subjects were directly interviewed, using the Schedulefor Affective Disordersand Schizophrenia-Lifetime Version and diagnosed according to Research Diagnostic Criteria (ROC ). Consensus diagnosis was made blind to the proband diagnoses by two psychiatrists, also based on any avalilable information from other sources (information from relatives and specialists, medicalrecords). We typed the D3 gene using Bal I enzyme site polymorphism in the first exon. This polymorphism reveals a 2 allele system withfrequencies of 0.68 and 0.32. A standard Chi-square test did not reveal any association between disease and DR03 genotypes; no association was detected using the Haplotype Relative Risk approach as modified by Terwillinger and Ott (I992)., in order to increase information about allelic associations by analyzing haplotype-based rather than genotypic based (Chi-square = 0.19, Odds ratio = 1.13). Likewise. transmission test for linkage disequilibrium (TOT) calculated by Mc Nemar's test yielded non-significant results (Chi-square = 0.12, P = 0.72) In conclusion, the candidate gene 03 does not appear to playa major role in the etiology of bipolaraffective disorder, in our Sardinian sample. References Nanko, S.• Fukuda. R.. Hattori, M., Sasaki. T.• Dai, X.Y.. Kanba, S.. Kato T. and
Kazamatsuri, H.{I994) Linkage studiesbetween affectivedisorder and dopamine ~. DJ and D4 receptor gene loci infour japanese pedigrees. Psychiatry Research 52.14<:l-157.
Parsian, A.. Chakraverty S.andTodd. R.O. (1995) Possible association between the dopamine OJ receptor gene andbipolar affectivedisorder. American Journal of Medical Genetics (Neuropsychiatric Genetics) 60. 234--237.
Terwillinger. J.D. and alt. J. (l992) A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. Human Heredity 42. 337-346 .
IP.3.031 IThepreclinical profile of an original pyridobenzoxazepine, JL 13 J.-F. Liegeois1.2, J. Bruhwyler3, AJ. Goudie4, A. Taylor4 ,J. Damas I, J. Delarge2, J. Geczy 3. I Laboratory of Physiology, Liege, Belgium; 2 Laboratory of Medicinal Chemistry. University of Liege, Liege, Belgium; 3 Therabel Research, Brussels, Belgium: 4 Laboratory of Psychology, University of Liverpool, Liverpool, United Kingdom
The demonstration that clozapine possesses both increased efficacy, particularly in treatment-resistant patients, and reduced neurotoxicity, however, has forever altered the conventional wisdom which held all antipsychotics were equally efficacious and uniformly neurotoxic. However,clozapinepresentsdifferent side effects (agranulocytosis, orthostatic hypotension, hypersalivation, seizures....) and its prescription is restricted
to patients whoare resistant to or intolerant of conventional antipsychotic drugs. So there remains a need for improved atypical antipsychotic drugs. In this context, a series of pyridobenzazepine derivatives has been synthesized and evaluated in various pharmacological procedures [1,2]. The researches have resulted in the selection of a promising compound, 8chloro-5-(4-methylpiperazin-l-y1)-pyrido[2,3-b][1,5]benzoxazepine fumarate(JL 13). The affinities for differentreceptors were reduced but its 5-HT2A1D2, D41D2 ratios were increased in comparisonwith clozapine. Like clozapine, JL 13 did not antagonize apomorphine-induced stereotypy and did not producecatalepsy but antagonize apomorphine-induced climbing. In the open-field and forced swimmingtests, JL 13 presents a similar profile with c1ozapine. In a temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without classical side effects. In a drugdiscrimination in the rat and in the squirrelmonkey, JL 13 produced a full substitution of c1ozapine. Throughthese preclinical data, JL 13 appears to be a very interesting potential antipsychotic drug. References
[1) Bruhwyler, J., Llegeois, J.-F.. Chleide, E., Register, E, Damas. J., Delarge, J. and MercierM. (l992) Comparative study of typical aeurolepdcs, clozapine and new synthesized clozapine analogues: correlations between neurochemistry and behaviour. Behavioural PbannacoI. 3, 567-579; [2] Liegeois, J.·F., Register, E. Bruhwyler, J., Damas, J., Nguyen, T.P., Inarejos, M.a.. Chleide, E., Mercier. M., Delarge, J. (l994) Pyridobenzoxazepine and pyridobenzothiazepine derivatives as potent central nervous system agents: synthesis andneurochemical study. J. Med. Chern. 37, 51<:l-525
IP.3.032! Rattardive dyskinesiais mediated by PlUnked 0·1 dopamine receptorsubtype
H. Rosengarten, AJ. Friedhoff. Mil/hauser Laboratories, Department of Psychiatry, New York University SchoolofMedicine 550 FirstAve, New York, N.r. 10016, USA Oral movements in rats resultingfrom chronic neuroleptic administration (Repetitive Jaw Movements) are the rat analogue of tardive dyskinesia whichresultsfrom chronic neuroleptic treatmentin humans. Repetitive jaw movements (RIM) can be induced in rats by a single administration of 0-1 agonist SKF 38393. 0-2 antagonists or administration of conventional neuroleptics for several months, analogous with several years of treatment needed to produce tardive dyskinesia in humans. These can be characterized as seemingly purposeless openings and closings of the jaw, with occasional tongue protrusions [1,2]. We have also demonstrated that reduction of the number of functional D-I receptors by ± 70% [3] by administering the peptide coupling agent N- ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ)did not affect RIM scores. Selectivity was achieved by prior administration of antagonists of those receptors that one wishes to spare from the irreversible effect of EEOQ. It has been found in our laboratory that the subtype of the D-I receptor linked to PI hydrolyis and formation of second messengers, not to c-AMP to which the dominant receptor is coupled, is resistant to EEDQ inactivation. We evaluated PI hydrolysis in caudate slices fromrats treatedwith vehicleor 6 mglkgofEEDQ. Eighteen hours after treatment rats were tested for the rate of RIM and caudate slices exposed to tritiated myoinositol and then incubated with0-1 agonist SKF 38393. PI hydrolysis and the rate of RIM were unaffected by EEDQ while D-I receptorbinding in the rat caudate showed expected 70-80% decrease in binding of the D-l antagonist, tritiated SCH 23390, showing that about 20-30% of D-l dopamine receptors producing RIM are linked to PI hydrolysis and formation of second messengers. By exposing the caudateslices to the D-l inhibitor, SCH23390.we observed the expected abolition ofPI hydrolysis. Furthermore. usinga D·I agonistpotenttoward c-AMP production but weak with respect to PI hydrolysis we actually drovePI hydrolysis belowbasal values. Thisstudyprovided evidence that rat tardivedyskinesia(RIM model)is elicited by a dopamineD-I receptorpathwaylinkedto secondmessengers derived from the hydrolysis of phosphoinositides. References [I] Rosengarten, H., Schweitzer. l.W. andAJ. Friedhoff. Induction oforal dyski-
54-112
IP.3.030 I No evidence of association between dopamine 03 receptorgeneand bipolar disorder in a sardinian sample G. Severino, M.A. Palmas, S. Ruiu,M. Del Zompo, P.Piccardi. Department ofNeurosciences "B.B. Brodie", University of Cagliari, Cagliari, Italy The dopamine OJ receptor is a candidate gene for psychiatric disorders. There have been several positive and negative reports regarding a potential role of dopamineD3 receptorgene locus (DR03) in bipolaraffective disorders. Linkage studies ruled out a D3 gene involvement in bipolar disorder (Nanko et al, 1993). Likewise, negative results were foundby association studies comparing bipolar patients with controls about its role in genetic predisposition to bipolaraffective disorder. However. Parsian et aI. (1995) have recently reported an association between bipolar affective disorder and DRO) using the haplotyperelative risk (HRR) approach. The potentialrelevance of the latterfinding promptedus to studyDR03 alleles in a sampleof 44 nuclearSardinian families with bipolardisorder. Forty-four unrelated probands, 12 Bipolar 1, II Bipolar II and 21 Schizoaffective Bipolar, with both parents alive were recruited from the Center of ClinicalPsychopharmacology of Department of Neurosciences "B. B. Brodie", University of Cagliari. Admission to the study was independent on family history. All probands, their parents and affected sibs gave informedconsent to participate in the study and to have venous blood sample drawn. All subjects were directly interviewed, using the Schedulefor Affective Disordersand Schizophrenia-Lifetime Version and diagnosed according to Research Diagnostic Criteria (ROC ). Consensus diagnosis was made blind to the proband diagnoses by two psychiatrists, also based on any avalilable information from other sources (information from relatives and specialists, medicalrecords). We typed the D3 gene using Bal I enzyme site polymorphism in the first exon. This polymorphism reveals a 2 allele system withfrequencies of 0.68 and 0.32. A standard Chi-square test did not reveal any association between disease and DR03 genotypes; no association was detected using the Haplotype Relative Risk approach as modified by Terwillinger and Ott (I992)., in order to increase information about allelic associations by analyzing haplotype-based rather than genotypic based (Chi-square = 0.19, Odds ratio = 1.13). Likewise. transmission test for linkage disequilibrium (TOT) calculated by Mc Nemar's test yielded non-significant results (Chi-square = 0.12, P = 0.72) In conclusion, the candidate gene 03 does not appear to playa major role in the etiology of bipolaraffective disorder, in our Sardinian sample. References Nanko, S.• Fukuda. R.. Hattori, M., Sasaki. T.• Dai, X.Y.. Kanba, S.. Kato T. and
Kazamatsuri, H.{I994) Linkage studiesbetween affectivedisorder and dopamine ~. DJ and D4 receptor gene loci infour japanese pedigrees. Psychiatry Research 52.14<:l-157.
Parsian, A.. Chakraverty S.andTodd. R.O. (1995) Possible association between the dopamine OJ receptor gene andbipolar affectivedisorder. American Journal of Medical Genetics (Neuropsychiatric Genetics) 60. 234--237.
Terwillinger. J.D. and alt. J. (l992) A haplotype-based 'haplotype relative risk' approach to detecting allelic associations. Human Heredity 42. 337-346 .
IP.3.031 IThepreclinical profile of an original pyridobenzoxazepine, JL 13 J.-F. Liegeois1.2, J. Bruhwyler3, AJ. Goudie4, A. Taylor4 ,J. Damas I, J. Delarge2, J. Geczy 3. I Laboratory of Physiology, Liege, Belgium; 2 Laboratory of Medicinal Chemistry. University of Liege, Liege, Belgium; 3 Therabel Research, Brussels, Belgium: 4 Laboratory of Psychology, University of Liverpool, Liverpool, United Kingdom
The demonstration that clozapine possesses both increased efficacy, particularly in treatment-resistant patients, and reduced neurotoxicity, however, has forever altered the conventional wisdom which held all antipsychotics were equally efficacious and uniformly neurotoxic. However,clozapinepresentsdifferent side effects (agranulocytosis, orthostatic hypotension, hypersalivation, seizures....) and its prescription is restricted
to patients whoare resistant to or intolerant of conventional antipsychotic drugs. So there remains a need for improved atypical antipsychotic drugs. In this context, a series of pyridobenzazepine derivatives has been synthesized and evaluated in various pharmacological procedures [1,2]. The researches have resulted in the selection of a promising compound, 8chloro-5-(4-methylpiperazin-l-y1)-pyrido[2,3-b][1,5]benzoxazepine fumarate(JL 13). The affinities for differentreceptors were reduced but its 5-HT2A1D2, D41D2 ratios were increased in comparisonwith clozapine. Like clozapine, JL 13 did not antagonize apomorphine-induced stereotypy and did not producecatalepsy but antagonize apomorphine-induced climbing. In the open-field and forced swimmingtests, JL 13 presents a similar profile with c1ozapine. In a temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without classical side effects. In a drugdiscrimination in the rat and in the squirrelmonkey, JL 13 produced a full substitution of c1ozapine. Throughthese preclinical data, JL 13 appears to be a very interesting potential antipsychotic drug. References
[1) Bruhwyler, J., Llegeois, J.-F.. Chleide, E., Register, E, Damas. J., Delarge, J. and MercierM. (l992) Comparative study of typical aeurolepdcs, clozapine and new synthesized clozapine analogues: correlations between neurochemistry and behaviour. Behavioural PbannacoI. 3, 567-579; [2] Liegeois, J.·F., Register, E. Bruhwyler, J., Damas, J., Nguyen, T.P., Inarejos, M.a.. Chleide, E., Mercier. M., Delarge, J. (l994) Pyridobenzoxazepine and pyridobenzothiazepine derivatives as potent central nervous system agents: synthesis andneurochemical study. J. Med. Chern. 37, 51<:l-525
IP.3.032! Rattardive dyskinesiais mediated by PlUnked 0·1 dopamine receptorsubtype
H. Rosengarten, AJ. Friedhoff. Mil/hauser Laboratories, Department of Psychiatry, New York University SchoolofMedicine 550 FirstAve, New York, N.r. 10016, USA Oral movements in rats resultingfrom chronic neuroleptic administration (Repetitive Jaw Movements) are the rat analogue of tardive dyskinesia whichresultsfrom chronic neuroleptic treatmentin humans. Repetitive jaw movements (RIM) can be induced in rats by a single administration of 0-1 agonist SKF 38393. 0-2 antagonists or administration of conventional neuroleptics for several months, analogous with several years of treatment needed to produce tardive dyskinesia in humans. These can be characterized as seemingly purposeless openings and closings of the jaw, with occasional tongue protrusions [1,2]. We have also demonstrated that reduction of the number of functional D-I receptors by ± 70% [3] by administering the peptide coupling agent N- ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ)did not affect RIM scores. Selectivity was achieved by prior administration of antagonists of those receptors that one wishes to spare from the irreversible effect of EEOQ. It has been found in our laboratory that the subtype of the D-I receptor linked to PI hydrolyis and formation of second messengers, not to c-AMP to which the dominant receptor is coupled, is resistant to EEDQ inactivation. We evaluated PI hydrolysis in caudate slices fromrats treatedwith vehicleor 6 mglkgofEEDQ. Eighteen hours after treatment rats were tested for the rate of RIM and caudate slices exposed to tritiated myoinositol and then incubated with0-1 agonist SKF 38393. PI hydrolysis and the rate of RIM were unaffected by EEDQ while D-I receptorbinding in the rat caudate showed expected 70-80% decrease in binding of the D-l antagonist, tritiated SCH 23390, showing that about 20-30% of D-l dopamine receptors producing RIM are linked to PI hydrolysis and formation of second messengers. By exposing the caudateslices to the D-l inhibitor, SCH23390.we observed the expected abolition ofPI hydrolysis. Furthermore. usinga D·I agonistpotenttoward c-AMP production but weak with respect to PI hydrolysis we actually drovePI hydrolysis belowbasal values. Thisstudyprovided evidence that rat tardivedyskinesia(RIM model)is elicited by a dopamineD-I receptorpathwaylinkedto secondmessengers derived from the hydrolysis of phosphoinositides. References [I] Rosengarten, H., Schweitzer. l.W. andAJ. Friedhoff. Induction oforal dyski-