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1.
J Phys Chem B ; 113(29): 9886-93, 2009 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-19569628

RESUMO

We have developed interatomic interaction parameters for Na+ and Cl- hydration using the dissociative water potential of Mahadevan and Garofalini [J. Phys. Chem. B 2007, 111, 8919] suitable for molecular dynamic simulations. Simulations were performed for small ion-water clusters Na(H2O)n+ (n=1-6) and Cl(H2O)m- (m=1-5), as well as dilute aqueous solutions of the ions in water, reproducing the structure and energies found in the literature. A simulation of an HCl molecule in water demonstrated the dissociation of the molecule. The Na+ and Cl- ion-ion interaction parameters also reproduce the energy and density of crystalline NaCl. A series of simulations of NaCl at progressively increasing temperatures from 300 to 1400 K produced solid densities varying by less than 1% from experiment.


Assuntos
Cloretos/química , Simulação por Computador , Modelos Químicos , Sódio/química , Água/química , Íons/química , Cloreto de Sódio/química , Temperatura
2.
Med Law ; 22(2): 311-27, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12889650

RESUMO

The compulsory treatment of people with substance use disorders continues to attract interest in many countries, particularly in the medico-legal, policy and research communities. Beyond the current fashion for Drugs Courts within the criminal justice system, several jurisdictions have for many years had involuntary commitment regimes operating within the civil sphere. This paper offers a case-study of one such regime that operates in New South Wales, Australia. After backgrounding the introduction of the Inebriates Act in the early 1900s, and describing the major features of the legislation, the paper outlines how the Act is currently being used, and what little is known about treatment outcomes under this regime. The paper concludes by considering a number of criticisms that have been levelled against the Inebriates Act, and briefly assessing its prospects for the future.


Assuntos
Alcoolismo/terapia , Programas Obrigatórios/legislação & jurisprudência , Alcoolismo/reabilitação , Humanos , New South Wales , Resultado do Tratamento
3.
J Med Chem ; 42(25): 5077-94, 1999 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-10602693

RESUMO

Several novel functionalized adamantyl aryl- and heteroarylpiperazine derivatives were prepared and examined in various receptor binding and behavioral tests to determine their serotonin receptor activities. Many compounds demonstrated modest to high affinity for 5-HT(1A) receptors, with compounds 9, 13, 23, 33, 34, and 43 being the most potent at this site. Compound 1, 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl adamantyl-1-carboxylate, demonstrated relatively high affinity for 5-HT(1A) receptors (K(i) = 8 nM) and acceptable selectivity versus D(2) receptors (K(i) = 708 mM); however, it lacked in vivo activity in serotonergic behavioral models. In contrast, compounds 9 (WY-50,324, SEB-324, adatanserin), adamantyl-1-carboxylic acid 2-[4-(2-pyrimidinyl)-1-piperazinyl]ethylamide, and 13, adamantyl-1-carboxylic acid 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethylamide, demonstrated high affinity for 5-HT(1A) binding sites (K(i) = 1 nM for both) and moderate affinity for 5-HT(2) receptors (K(i) = 73 and 75 nM, respectively). Both compounds also demonstrated partial 5-HT(1A) agonist activity in vivo in rat serotonin syndrome and 5-HT(2) antagonist activity in quipazine- and DOI-induced head shake paradigms. The selective 5-HT(1A) partial agonist and 5-HT(2) antagonist activity of 9 was accompanied by significant anxiolytic activity in an animal conflict model. On the basis of this profile, compound 9 entered development as a combined anxiolytic and antidepressant agent.


Assuntos
Ansiolíticos/síntese química , Antidepressivos/síntese química , Piperazinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Animais , Ansiolíticos/química , Ansiolíticos/farmacologia , Antidepressivos/química , Antidepressivos/farmacologia , Masculino , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/classificação , Análise Espectral , Relação Estrutura-Atividade
4.
J Med Chem ; 42(11): 2007-20, 1999 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-10354409

RESUMO

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.


Assuntos
Agonistas de Dopamina/química , Etilaminas/química , Indóis/química , Receptores de Dopamina D2/metabolismo , Animais , Ligação Competitiva , Corpo Estriado/metabolismo , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Etilaminas/síntese química , Etilaminas/metabolismo , Etilaminas/farmacologia , Hipocampo/metabolismo , Técnicas In Vitro , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacologia , Camundongos , Modelos Moleculares , Conformação Molecular , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Eur Respir J ; 12(2): 477-82, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9727805

RESUMO

The results obtained using deoxyribonucleic acid (DNA) amplification-based tests must be accurate and reproducible. One such test that simultaneously detects any of 12 of the most common mutations of the cystic fibrosis transmembrane conductance regulator gene is presented in this report. An investigation was conducted into how changes of primer, DNA template and Taq DNA polymerase concentrations and of polymerase chain reaction annealing temperatures affect the test. A total of 383 DNA samples obtained from different laboratories was then examined. The preliminary studies defined the conditions under which accurate results are obtained even if the test is performed under suboptimal conditions. Subsequently, 377 (98.4%) of the DNA samples analysed were in full agreement with DNA typing results derived by other methods. The remaining 1.6% of samples were not mistyped, rather they were not scored owing to failure to detect control DNA sequences. These were also archival DNA preparations rather than freshly prepared samples from venous blood. Careful primer design and optimization of reaction conditions are important in the development of multiplex deoxyribonucleic acid amplification-based diagnostic tests. Providing the recommended protocols are followed, the test described here is simple to carry out, gives accurate results and works well if performed within defined operational windows for each reaction variable.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/prevenção & controle , Testes Genéticos/métodos , Fibrose Cística/genética , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Testes Genéticos/normas , Humanos
7.
Bioorg Med Chem Lett ; 8(3): 295-300, 1998 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-9871673

RESUMO

Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonists as well as templates for the future design of novel dopaminergic agents.


Assuntos
Agonistas de Dopamina/química , Fenóis/química , Piperazinas/química , Agonistas de Dopamina/farmacologia , Fenóis/síntese química , Fenóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Dopamina D2/agonistas , Relação Estrutura-Atividade
8.
J Med Chem ; 40(26): 4235-56, 1997 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-9435894

RESUMO

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.


Assuntos
Cromanos/síntese química , Dopaminérgicos/síntese química , Receptores de Dopamina D2/agonistas , Animais , Células CHO , Cromanos/química , Cromanos/farmacologia , Cricetinae , Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
9.
Br J Cancer ; 74(11): 1796-800, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8956795

RESUMO

One hundred and sixty-three breast carcinomas occurring in women aged between 26 and 44 years were examined for pathological features, oestrogen and progesterone receptor status, proliferation as determined by Ki-67 labelling and the presence of c-erbB-2 and p53 protein, and were compared with a control group of carcinomas from women in the 50-67 years age group. Carcinomas occurring in women aged under 35 years had a significantly high incidence of being poorly differentiated and of having high proliferation rates. This group also had a significantly high incidence of p53 protein staining. Carcinomas in the under 30 years age group had a lower incidence of oestrogen and progesterone receptor positivity. No differences were found in c-erbB-2-positive staining between the groups. Infiltrating lobular carcinomas were only identified in women aged 40 years and over. There was a higher incidence of a family history in the 35-44 years age group (18%) than in the under 35 years age group (11%). Breast carcinomas occurring in women aged under 35 years are more aggressive. An important finding is the high incidence of p53 positivity, which may indicate genetic instability.


Assuntos
Neoplasias da Mama , Adulto , Distribuição por Idade , Fatores Etários , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/química , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Saúde da Família , Feminino , Humanos
10.
J Forensic Sci ; 39(2): 526-31, 1994 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8195763

RESUMO

In this paper we report the identification of an individual using the MVR-PCR technique on DNA extracted from single and multiple discs (3 mm) punched from a licked stamp attached to an envelope. The individual's code was successfully and uniquely matched to one already present within a database of 500 MVR codes which had been generated in a separate laboratory. The exercise illustrates the suitability of MVR-PCR for forensic samples and demonstrates the power of this rapid and novel identification system.


Assuntos
DNA Satélite , Medicina Legal/métodos , Filatelia , Reação em Cadeia da Polimerase/métodos , Sequências Repetitivas de Ácido Nucleico/genética , Saliva/química , Bases de Dados Factuais , Estudos de Avaliação como Assunto , Humanos , Grupos Raciais/genética , Sensibilidade e Especificidade
11.
J Forensic Sci ; 38(5): 1172-5, 1993 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8228884

RESUMO

DNA probes commonly used for forensic DNA profiling analysis were hybridized to Hinfl digested DNA isolated from various common microbial species. Extended exposures to light sensitive film failed to detect any DNA fragments of a microbial origin following hybridizations to radio-labeled DNA insert single-locus probes (SLPs) and nonisotopically labeled oligonucleotide SLPs.


Assuntos
Impressões Digitais de DNA , DNA Bacteriano/análise , DNA Fúngico/análise , Sequências Repetitivas de Ácido Nucleico , Sondas de DNA , Reações Falso-Positivas , Humanos
12.
Dev Biol Stand ; 76: 39-42, 1992.
Artigo em Inglês | MEDLINE | ID: mdl-1478352

RESUMO

DNA fingerprinting using multi-locus probes has become established as the most powerful technology for the identification and characterisation of mammalian cell lines. However, care must be taken in the technical preparation and statistical evaluation of the DNA banding patterns.


Assuntos
Linhagem Celular , Impressões Digitais de DNA , Animais , Humanos
13.
Mol Gen Genet ; 215(1): 156-60, 1988 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3149398

RESUMO

A segment of the Escherichia coli genome which complements the ionising radiation sensitivity of the rorB mutation was cloned into pBR322. This DNA segment also complements the mitomycin C sensitivity of the rorB mutation. The gene was subcloned until defined in a fragment of 1.05 kb. Only one gene product, a protein of approximately 16.5 kDa, was found on maxicell analysis of the various subclones. Iso-electric focusing of this gene product suggests it may function in a complex.


Assuntos
Reparo do DNA , DNA Bacteriano/genética , Escherichia coli/genética , Genes Bacterianos , Clonagem Molecular , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/efeitos da radiação , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Teste de Complementação Genética , Mitomicina , Mitomicinas/farmacologia , Mutação
14.
Mol Gen Genet ; 215(1): 161-4, 1988 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-3149399

RESUMO

Escherichia coli K803 cells were mutagenized and screened for the presence of clones sensitive to gamma-rays but not to ultraviolet light. One new mutant of this type, named rorB, was isolated. This mutant is both cross-sensitive to mitomycin C and shows reduced conjugal recombination frequencies, but to a lesser extent than the phenotypically similar mutant recN. Unlike previously reported mutants of E. coli or yeast with an enhanced sensitivity to ionising radiations, rorB appears to be near wild type in ability to rejoin DNA double-strand breaks. The rorB gene maps close to ilvGEDAC at 84.5 min of the E. coli chromosome.


Assuntos
Reparo do DNA/efeitos da radiação , DNA Bacteriano/efeitos da radiação , Escherichia coli/genética , Reparo do DNA/efeitos dos fármacos , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/genética , Escherichia coli/metabolismo , Escherichia coli/efeitos da radiação , Raios gama , Genes Bacterianos , Mitomicina , Mitomicinas/farmacologia , Mutação , Raios Ultravioleta
15.
Somat Cell Mol Genet ; 14(6): 519-25, 1988 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2904177

RESUMO

Hypervariable DNA sequences may be used as probes to derive DNA "finger-prints" for individuals. To assess the use of the human 33.15 and 33.6 probes (isolated by Jeffreys and coworkers) for characterizing cell lines of nonhuman origin, DNA from different stocks of Chinese hamster (CH) cells was screened. All CHO (ovary) sublines could be readily distinguished from CH-V79 sublines by their fingerprints, but where two stocks had been derived recently from the same line, their fingerprints were nearly identical. Similarly fingerprints of HPRT-deficient mutants derived from one cell stock were identical. A V79 x CHO fusion hybrid showed equal fingerprint band-sharing with each parent line, while early-passage diploid CH cells had a fingerprint closer to CHO than to V79. Thus these data introduce a simple means of typing cell lines to avoid cross-contamination, of checking cell hybrids, and of assessing the divergence of cell stocks from one another.


Assuntos
Cricetinae/genética , Cricetulus/genética , Sondas de DNA , Polimorfismo Genético , Polimorfismo de Fragmento de Restrição , Animais , Southern Blotting , Linhagem Celular , Células Híbridas , Especificidade da Espécie
16.
J Med Chem ; 31(7): 1382-92, 1988 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2898533

RESUMO

A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.


Assuntos
Ansiolíticos , Imidas/síntese química , Piperazinas/síntese química , Receptores de Serotonina/metabolismo , Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Química , Imidas/metabolismo , Imidas/farmacologia , Masculino , Piperazinas/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D2 , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
17.
Mutat Res ; 199(1): 145-58, 1988 May.
Artigo em Inglês | MEDLINE | ID: mdl-3362156

RESUMO

A series of vectors with two dominant selectable genes was constructed for repair and mutation studies following transfer into mammalian cells. The recombinant genes (SV-gpt and HSVtk-neo) were placed in different relative orientations and positions in the vectors. These variables were shown to affect transformation frequency of cells by the vectors especially where one of the genes had a relatively weak expression, modelled by truncating the promoter of the HSVtk-neo gene. The use of two-gene vectors to assess DNA repair was investigated by cutting the SV-gpt gene with a restriction endonuclease and monitoring correct rejoining by selecting for gene activity after transfer into various cell types. In such experiments, selection was first applied for the undamaged HSVtk-neo gene to eliminate transfer artefacts, followed by counterselection for the activity of the damaged SV-gpt gene. The measured frequency of correct rejoining of the damaged gene was found to vary both with the vector construct and with the recipient cell species (Chinese hamster V79 or human transformed fibroblasts). Despite this variation, correct rejoining was found to be consistently lower in radiosensitive (ataxia telangiectasia) human cells than in wild-type human cells, irrespective of the vector construct. In these experiments, some of the transformed cell colonies showed 'sectoring' on exposure to the counterselection, suggesting a slow determination of the fate of transferred DNA. For mutation studies a V79 cell clone carrying a single copy of one of these two-gene vectors was identified and shown to be stably integrated. Mutations of the SV-gpt gene in these cells were isolated while maintaining selection for the HSVtk-neo gene, to attempt to limit mutational loss of the total integrated sequence and provide at least one identifiable junction for analysis of deletion events. Spontaneous and X-ray-induced mutants were identified with a variety of genetic changes, as shown by Southern analysis, from presumed point mutations to deletions and rearrangements of the vector sequence. Rescue of integrated two-gene vector sequences from transformed cells, by recloning in E. coli, was shown to be feasible; thus alterations in transferred DNA can be analysed in detail.


Assuntos
Reparo do DNA , Vetores Genéticos , Testes de Mutagenicidade , Animais , Linhagem Celular , Cricetinae , DNA Recombinante , Humanos , Técnicas In Vitro , Plasmídeos , Transformação Genética
18.
Mutat Res ; 199(1): 1-9, 1988 May.
Artigo em Inglês | MEDLINE | ID: mdl-2834642

RESUMO

DNA double-strand break repair was assessed in 2 new radiation-sensitive V79 hamster cell lines (irs1 and irs2) by their ability to rejoin restriction endonuclease cuts in a transferred selectable SV40--E. coli gpt recombinant gene. The studied gene was carried in the vector pPMH16 which also contained a second selectable HSVtk-neo recombinant gene which acted as a control for DNA transformation. The parental V79 cells showed correct rejoining of KpnI and EcoRV double-strand breaks in approximately 18% and 36% of transformants respectively (correcting for the expression of undamaged gpt in neo+ transformants). irs1 shows a significantly reduced (approximately 3-fold) ability to rejoin correctly such double-strand scissions. However, irs2 rejoined such lesions as correctly as the V79 cells. The data are discussed in the context of the assay and the possible repair deficiencies of these radiosensitive mutant cells.


Assuntos
Reparo do DNA , Animais , Linhagem Celular , Cricetinae , Enzimas de Restrição do DNA/metabolismo , DNA Recombinante , Vetores Genéticos , Radiação Ionizante , Transformação Genética
19.
J Med Chem ; 30(10): 1818-23, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2888898

RESUMO

Several novel substituted gamma-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity. Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior. Compound 17 (Wy-47,384), a gamma-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests. It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip). Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.


Assuntos
Antipsicóticos/farmacologia , Carbolinas/farmacologia , Animais , Antipsicóticos/síntese química , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Carbolinas/síntese química , Masculino , Camundongos , Ratos , Receptores Dopaminérgicos/metabolismo , Espiperona/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
20.
J Cell Sci Suppl ; 6: 177-89, 1987.
Artigo em Inglês | MEDLINE | ID: mdl-2821021

RESUMO

We have utilized DNA transfer and recombinant DNA techniques to probe DNA double-strand break repair in the human ionizing radiation-sensitive genetic syndrome ataxia-telangiectasia (A-T). Using restriction enzyme-generated double-strand breaks in the coding sequence of a selectable gene we have detected a significantly greater frequency of mis-repair of such breaks in a permanent A-T cell line compared with cell lines of normal radiosensitivity. This mis-repair in A-T can plausibly explain many of the clinical features of the disease but was insufficiently detailed to address the broad problem of DNA repair mechanisms relevant to ionizing radiation-induced damage. To extend these observations of DNA double-strand break mis-repair we have now applied this type of repair assay to novel, de novo induced mammalian X-ray-sensitive cell lines and to appropriate Escherichia coli mutants. In both cellular systems we have now found some equivalence to the A-T repair defect. In particular, studies on one E. coli mutant have provided evidence suggesting an involvement of a topoisomerase activity in DNA double-strand break mis-repair, which may be relevant to the biochemical defect in A-T.


Assuntos
Ataxia Telangiectasia , Reparo do DNA , Linhagem Celular , DNA/metabolismo , DNA/efeitos da radiação , DNA Topoisomerases Tipo II/metabolismo , Humanos , Fenótipo , Tolerância a Radiação , Raios X
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