RESUMO
The synthesis and antihypertensive activity of a series of novel 4-(cyclic amido)-2H-1-benzopyran-3-ols, administered orally to conscious spontaneously hypertensive rats, are described. The effects of lactam ring size, the presence of heteroatoms in the lactam ring, substitution at C(2) and C(3), relative stereochemistry at C(3) and C(4), and aromatic substitution pattern on the blood pressure lowering activity of this series have been determined. The key compound 2 from this work [BRL 34915; (+/-)-6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxopyrrolidin-1- yl)-2H-1-benzopyran-3-ol] has been resolved, and antihypertensive activity was found to reside primarily in the (-) enantiomer. The key step in the preparation of this class of compounds is the action of a cyclo amidic anion on an appropriate epoxide. Another approach, involving a cyclization step to the lactam was found to be more convenient in certain cases, particularly in forming the cis analogue of compound 2. Compound 2 has been shown to possess a novel mechanism of action, and it has been selected for progression to the clinic.
Assuntos
Anti-Hipertensivos/síntese química , Benzopiranos/síntese química , Animais , Anti-Hipertensivos/farmacologia , Benzopiranos/farmacologia , Ratos , Ratos Endogâmicos SHR , Relação Estrutura-AtividadeRESUMO
A selective dopamine D(3) receptor antagonist offers the potential for an effective antipsychotic therapy, free of the serious side effects of currently available drugs. Using clearance and brain penetration studies as a screen, a series of 1,2,3, 4-tetrahydroisoquinolines, exemplified by 13, was identified with high D(3) affinity and selectivity against the D(2) receptor. Following examination of molecular models, the flexible butyl linker present in 13 was replaced by a more conformationally constrained cyclohexylethyl linker, leading to compounds with improved oral bioavailability and selectivity over other receptors. Subsequent optimization of this new series to improve the cytochrome P450 inhibitory profile and CNS penetration gave trans-N-[4-[2-(6-cyano-1, 2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolinecarbo xamide (24, SB-277011). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and brain penetration in the rat and represents an excellent new chemical tool for the investigation of the role of the dopamine D(3) receptor in the CNS.
Assuntos
Sistema Nervoso Central/metabolismo , Antagonistas de Dopamina/síntese química , Nitrilas/síntese química , Quinolinas/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Tetra-Hidroisoquinolinas , Animais , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Catalepsia/induzido quimicamente , Catalepsia/psicologia , Sistema Nervoso Central/efeitos dos fármacos , Cricetinae , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacologia , Meia-Vida , Humanos , Masculino , Microdiálise , Nitrilas/farmacocinética , Nitrilas/farmacologia , Prolactina/sangue , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3RESUMO
Mice that were homozygous recessive for the single-gene mutation, hotfoot, showed profound and progressive motor disturbances in an open field after approximately the 4th postnatal week. Studies were undertaken to examine the role of the monoaminergic system in the behavioral and developmental expression of this neurological mutation. Relative to controls, 10-and 30-day-old hotfoot mice demonstrated a significantly attenuated response to the stimulating locomotor effects of amphetamine while adult hotfoot mice were motorically unaffected by amphetamine administration. 30-day-old and adult hotfoot mice also were hypothermic relative to phenotypically normal mice after amphetamine administration. Examination of monoamine levels and turnover revealed that hotfoot mice had significantly greater concentrations of norepinephrine associated with lower turnover in cerebellum and greater levels of serotonin in cerebellum and striatum, relative to phenotypic controls. In addition, mice born and raised by hotfoot dams demonstrated neurochemical alterations regardless of genotype. Both the neurochemical data and the developmental response to the general catecholamine agonist, amphetamine, suggest that the monaminergic neurotransmitter system may be altered as a consequence of the hotfoot mutation.
Assuntos
Ataxia/genética , Ataxia/metabolismo , Monoaminas Biogênicas/metabolismo , Sistema Nervoso Central/metabolismo , Atividade Motora/fisiologia , Mutação , Envelhecimento/fisiologia , Anfetamina/farmacologia , Animais , Temperatura Corporal , Peso Corporal , Cerebelo/metabolismo , Corpo Estriado/metabolismo , Genótipo , Camundongos , Camundongos Mutantes Neurológicos/genética , Atividade Motora/efeitos dos fármacos , Neurotransmissores/metabolismoRESUMO
The dopaminergic system has long been implicated in the mechanisms of reward and addiction. 1-(4-(2-Naphthoylamino)butyl)-4-(2-methoxyphenyl)-1A-piperazine HCl (BP 897) has been claimed to be a selective dopamine D3 receptor partial agonist and has recently been shown to inhibit cocaine-seeking behaviour, suggesting a role for dopamine D3 receptor agonists in the treatment of addiction. We have previously characterised the pharmacological profile of the human dopamine D3 and D2(long) receptors using microphysiometry and radioligand binding and we have now studied the interaction of BP 897 with the dopamine D2 and D3 receptors using these methods. At both human dopamine D3 and D2 receptors, BP 897 lacked agonist activity but was a potent and selective antagonist with pK(b) values of 8.05+/-0.16 (4) and 9.43+/-0.22 (4) at human dopamine D2 and D3 receptors, respectively. These results, therefore, suggest that it may be the dopamine D3 receptor antagonist properties of BP 897 which have potential in the treatment of addiction and withdrawal.
Assuntos
Agonistas de Dopamina/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Azepinas/farmacologia , Células CHO , Cricetinae , Humanos , Quimpirol/farmacologia , Receptores de Dopamina D2/fisiologia , Receptores de Dopamina D3RESUMO
We examined susceptibility of several strains of mice to Eimeria separata. Mice of the following coat-color genotypes were inoculated with 2 X 10(4) sporulated oocysts of E. separata isolated from Rattus norvegicus: random-bred (aabbCC and A-bbCC), Balb/C (AAbbcc), Balb/Gw (AABBcc), Z/Gw (aaBBcc), and Swiss NLW (cc). Allele designations are A = agouti, a = nonagouti, B = black, b = brown, C, c = albino. Eimeria separata completed its life cycle with oocyst production in all male and female random-bred (aabbCC), Balb/Gw and G/Gw mice. The reproductive index of E. separata in Balb/Gw mice was significantly lower (P less than or equal to 0.05) than that of the other mouse strains. Among the random-bred mice, E. separata had a significantly lower (P less than or equal to 0.05) mean reproductive index in male than in female hosts. Patent period and oocyst length/width indices remained constant irrespective of host genus. This is the first documentation that genetic factors play a role in susceptibility of mice to the rat coccidium, E. separata.
Assuntos
Coccidiose/transmissão , Eimeria/crescimento & desenvolvimento , Camundongos/genética , Ratos/genética , Animais , Coccidiose/genética , Suscetibilidade a Doenças , Feminino , Masculino , Camundongos/parasitologia , Ratos/parasitologia , Especificidade da EspécieAssuntos
Animais Recém-Nascidos/efeitos da radiação , Comportamento Animal , Efeitos da Radiação , Análise de Variância , Animais , Peso Corporal/efeitos da radiação , Defecação/efeitos da radiação , Feminino , Genética Comportamental , Genótipo , Locomoção/efeitos da radiação , Masculino , Camundongos , Fatores Sexuais , Micção/efeitos da radiaçãoAssuntos
Modelos Animais de Doenças , Hiperglicemia/genética , Camundongos Endogâmicos/genética , Camundongos Mutantes/genética , Animais , Glicemia , Composição Corporal , Peso Corporal/fisiologia , Feminino , Hiperglicemia/sangue , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos/crescimento & desenvolvimento , Camundongos Mutantes/crescimento & desenvolvimento , FenótipoAssuntos
Animais Recém-Nascidos , Efeitos da Radiação , Reprodução/efeitos da radiação , Animais , Relação Dose-Resposta à Radiação , Feminino , Genótipo , Hibridização Genética , Expectativa de Vida , Tamanho da Ninhada de Vivíparos/efeitos da radiação , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Biológicos , Gravidez , Fatores Sexuais , Razão de Masculinidade , Raios XRESUMO
A malformation that resulted in the formation of 2 complete tails is described in a mouse that was heterozygous for the sex-linked gene Bent-tail (Bn). One of the tails appeared normal and contained 29 vertebrae, whereas the other tail consisted of 27 vertebrae and had several bends or kinks in it and also had malformed vertebrae similar to those described for the Bn gene. A comparison of the malformation with previously described bifurcated tail conditions in the mouse is presented. It is possible that this 2-tailed mouse represents a special case of X-chromosome inactivation.
Assuntos
Camundongos , Cauda/anormalidades , Animais , Feminino , Genes , Heterozigoto , MasculinoRESUMO
Development of 13 reflex responses and behavioral components of mice from the Goodale Giant inbred strain (G/Gw) was compared to that of a sample of 61 pups from a random-bred strain. Significant differences were observed between groups for several responses, but the direction of these differences was not consistent. Effects of rapid growth and increased size in G/Gw mice did not directly affect behavioral maturation.
Assuntos
Comportamento Animal , Peso Corporal , Camundongos Endogâmicos/genética , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos/crescimento & desenvolvimento , Fenótipo , Fatores SexuaisRESUMO
Ontogenetic and adult behavioral tests were conducted on an extreme non-agouti strain of mice carrying the Miwh mutation. Except for startle response, no significant differences were seen in any aspect of the preweaning reflex and neuromuscular tests. The lack of startle response seen in Miwh/Miwh and Miwh/+ mice can be attributed to abnormalities found in the inner ear of these genotypes. Among adult mice, significant differences were found in the open field and visual cliff tests.
Assuntos
Comportamento Animal , Genótipo , Animais , Percepção Auditiva , Percepção de Profundidade , Comportamento Exploratório , Genética Comportamental , Camundongos , Camundongos Mutantes Neurológicos , Reflexo , Reflexo de Sobressalto , Percepção VisualRESUMO
Paddle is a lethal, single recessive gene mutation in the mouse which results in a large median cleft palate and chondrodystrophy. Comparative cephalometric measurements on the growth of the normal and paddle fetal craniofacial complexes were made to determine the cause of cleft palate in paddle. Two methods of cephalometric measurements were used with 20 parameters analyzed. Both methods revealed a reduction in maxillary and mandibular growth, and a reduced cranial base angle which did not allow forward movement of the tongue under the primary palate, and hence obstructed shelf movement.
Assuntos
Fissura Palatina/embriologia , Animais , Cefalometria , Fissura Palatina/genética , Genes Recessivos , Mandíbula/embriologia , Maxila/embriologia , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Palato/embriologia , Língua/embriologiaRESUMO
Effects of abnormal neural tube development were studied in immature and adult mice. The behavior of affected adult mice was found to resemble that of mice that exhibit the "waltzer syndrome." Behavioral ontogenetic studies indicate that effected mice are deficient in labyrinthine responses as shown by the late development or lack of negative geotaxic behaviors and the delayed loss of pivoting behavior. Retarded maturation of neural responses was indicated by a delay in the appearance of the startle response. Evidence that circling behavior in adult mice of the "waltzer syndrome" may be a result of central nervous system disorders alone, or in concert with abnormalities of the inner ear, was provided by the fact that open field activity was increased in affected mice that exhibit circling behavior as adults.
Assuntos
Comportamento Animal/fisiologia , Defeitos do Tubo Neural/fisiopatologia , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Atividade Motora/fisiologia , Destreza Motora/fisiologia , Reflexo/fisiologiaRESUMO
1. The blood serum proteins of five species of Nearctic squirrels were electrophoretically examined. 2. Protein polymorphism was detected in all the species described. 3. The use of the mean relative mobility of specific proteins was shown to be a valuable aid in distinguishing species.