RESUMO
The 12/15-lipoxygenase (12/15LO) enzyme is widely distributed within the central nervous system. Previous work showed that this protein is upregulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in amyloid beta (Aß)-precursor protein transgenic mice (Tg2576). In the present paper, we studied the effect of its pharmacologic inhibition on the AD-like phenotype of a mouse model with plaques and tangles, the triple-transgenic mice. Compared with mice receiving placebo, the group treated with PD146176, a specific 12/15LO inhibitor, manifested a significant improvement of their memory deficits. The same animals had a significant reduction in Aß levels and deposition, which was secondary to a decrease in the ß-secretase pathway. In addition, while total tau-soluble levels were unchanged for both groups, PD146176-treated mice had a significant reduction in its phosphorylation state and insoluble fraction, which specifically associated with decrease in stress-activated protein kinase/c-Jun N-terminal kinase activity. In vitro study showed that the effect on tau and Aß were independent from each other. These data establish a functional role for 12/15LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 12/15LO inhibitors as novel therapeutic agents for AD.
Assuntos
Doença de Alzheimer/complicações , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Inibidores Enzimáticos/uso terapêutico , Fluorenos/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Tumoral , Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação/genética , Neuroblastoma/patologia , Presenilina-1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Proteínas tau/genéticaRESUMO
A series of tetrahydropyrrolo[1,2-a]quinoxalines and tetrahydropyrrolo[1,2-a]pyrido[3,2-a]pyrazines were synthesized and tested for their ability to relax K+-depolarized aortic smooth muscle and antihypertensive activity. It was shown that compounds producing the most relaxation of aortic smooth muscle (5-[2,6-dimethoxyphenyl)methyl]-1,2,3,3a-tetrahydropyrrolo[1,2-a] quinoxalin-4(5H)-one and 5-[(2,6-dimethoxyphenyl)methyl]-5,6,6a,7,8,9-hexahydropyrrolo[1,2- a] pyrazine, 10 and 19, respectively) demonstrated the least hypotensive activity. Those compounds that were the most effective hypotensive agents (6a,7,8,9-tetrahydro-5-(phenylmethyl)pyrido[3,2-a]pyrrolo[1,2-a]++ +pyrazin- 6(5H)-one and 6a,7,8,9-tetrahydro-5-(4-pyridinylmethyl)pyrido[3,2-e]pyrrolo [1,2-a]pyrazin-6(5H)-one, 12 and 13, respectively) displayed little vascular smooth muscle relaxant activity.
Assuntos
Anti-Hipertensivos/síntese química , Músculo Liso Vascular/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/síntese química , Pirazinas/síntese química , Pirróis/síntese química , Quinoxalinas/síntese química , Animais , Aorta Torácica/efeitos dos fármacos , Fenômenos Químicos , Química , Feminino , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Relaxamento Muscular/efeitos dos fármacos , Rotação Ocular , Pirazinas/farmacologia , Pirróis/farmacologia , Quinoxalinas/farmacologia , Coelhos , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
A series of novel substituted beta-carbolines was synthesized and tested for potential antipsychotic activity. Several compounds displayed moderate antipsychotic activity in vitro and in vivo as determined by relevant receptor binding assays and behavioral tests. The effect of substituents on antipsychotic activity was examined. The beta-carbolines 10 and 19 containing 2-(2-pyridinyl)ethyl and 2-(2-quinolinyl)ethyl side chains were the most potent analogues, blocking discrete trial conditioned avoidance responding in rats with AB50's of 23 and 10 mg/kg, respectively. Both showed moderate activity at the D2 receptor sites, but they lacked oral activity. In contrast, the beta-carboline 13 containing the 4-(4-pyridinyl)butyl side chain exhibited oral activity in the discrete trial conditioned avoidance screen with an AB50 of 31 mg/kg. Most compounds did not antagonize apomorphine-induced stereotyped behavior, which is indicative of low potential for extrapyramidal side effect (EPS) liability.
Assuntos
Antipsicóticos/síntese química , Carbolinas/síntese química , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Carbolinas/farmacologia , Masculino , Camundongos , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Structural manipulation of polycyclic piperazinyl imide serotonergic agents led to the synthesis of compound 8, 2-[4-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-4, 4a,5,5a,6,6a-hexahydro-4,6-ethenocycloprop[f]isoindole-1,3(2H,3 aH)-dione, which demonstrated good H1-antagonist activity. Substitution of a xanthinyl moiety for the polycyclic imide group led to the identification of novel xanthinyl-substituted piperazinyl and piperidinyl derivatives with potent antihistamine H1-activity without the undesirable antidopaminergic activity of 8. One compound, 24, 7-[3-[4-(diphenylmethoxy)-1-piperidinyl]propyl]- 3,7-dihydro-1,3-dimethyl-1H-pyrine-2,6-dione (WY-49051), is a potent, orally active H1-antagonist with a long duration of action and a favorable central nervous system profile.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Animais , Cobaias , Técnicas In Vitro , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Several novel substituted tetrahydro- and hexahydro-1,2-benzisothiazol-3-one 1,1-dioxides and thiadiazinones were prepared and examined in a series of in vitro and in vivo tests to determine their pharmacological profile. Most compounds were orally active in blocking the conditioned avoidance response (CAR) but did not antagonize apomorphine-induced stereotyped behavior. Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site, with compounds 37 and 38 containing 2-pyrimidinylpiperazinyl and [3-(trifluoromethyl)phenyl]piperazinyl moieties and compound 47 containing the 2-pyrazinylpiperazinyl moiety displaying the highest affinity (Ki values of 10, 4, and 9 nM, respectively). Compound 37, 3-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4, 7-etheno-1H-cyclobut [f]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, buspirone, and ipsapirone showed similarities in their neurochemical and behavioral profiles. They were similar in potency in blocking CAR with AB50 values of 39, 32, and 42 mg/kg, respectively. They also demonstrated high affinity and selectivity for the 5-HT1A receptor site (Ki = 10 nM) and exhibited partial agonist/antagonist activity in the serotonin syndrome test. In addition, compound 37 inhibited apomorphine-induced climbing behavior much more potently (ED50 of 3.4 mg/kg) than stereotyped behavior (ED50 of 32.2 mg/kg) and will be evaluated further. Structure-activity relationships within this series of compounds are discussed.
Assuntos
Ansiolíticos/síntese química , Óxidos S-Cíclicos/síntese química , Tiadiazinas/síntese química , Tiazinas/síntese química , Tiazóis/síntese química , Animais , Ansiolíticos/farmacologia , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Óxidos S-Cíclicos/farmacologia , Técnicas In Vitro , Masculino , Ratos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D2 , Receptores de Serotonina/efeitos dos fármacos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade , Tiadiazinas/farmacologia , Tiazóis/farmacologiaRESUMO
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-AtividadeRESUMO
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-AtividadeRESUMO
A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.
Assuntos
Benzimidazóis/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Fármacos Neuroprotetores/síntese química , Propionatos/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Arteriopatias Oclusivas/complicações , Benzimidazóis/química , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Ligação Competitiva , Encéfalo/metabolismo , Encéfalo/patologia , Doenças das Artérias Carótidas/complicações , Avaliação Pré-Clínica de Medicamentos , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Técnicas In Vitro , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Masculino , Camundongos , Modelos Moleculares , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacologia , Organofosfonatos , Propionatos/química , Propionatos/metabolismo , Propionatos/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/metabolismo , EstereoisomerismoRESUMO
The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Ciclobutanos/química , Aminoácidos Excitatórios/química , N-Metilaspartato/antagonistas & inibidores , Animais , Compostos Azabicíclicos , Compostos Bicíclicos Heterocíclicos com Pontes/química , Ciclobutanos/metabolismo , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Aminoácidos Excitatórios/metabolismo , Ataque Isquêmico Transitório/metabolismo , Ataque Isquêmico Transitório/patologia , Camundongos , Modelos Químicos , Organofosfonatos , Ácidos Pipecólicos/química , Ácidos Pipecólicos/metabolismo , Piperazinas/química , Piperazinas/metabolismo , RatosRESUMO
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-AtividadeRESUMO
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-AtividadeRESUMO
The synthesis of eight fluorene-9-spiro-2'-(N-aryl-3' ,3'-dichloroaziridines) was achieved via the reaction of dichlorocarbene with the appropriately substituted N-fluorenylideneanilines. Hydrolysis of the spirofluorenes afforded the corresponding 9-chlorofluorene-9-carboxanilides in excellent yields.
Assuntos
Aziridinas/síntese química , Azirinas/síntese química , Fluorenos/síntese química , Hidrólise , Compostos de Espiro/síntese químicaRESUMO
Dehydroepiandrosterone sulfatide was prepared in a 68% yield by the reaction of 5-androstene-3 beta-ol-17-one 3 sulfate (silver salt) with dipalmitoyl alpha-iodopropylene glycol. The sulfatide was found to be a more potent inhibitor of human glucose-6-phosphate dehydrogenase than dehydroepiandrosterone. 16 alpha-Halogenated steroids also were prepared by direct halogenation of the steroid or indirect halogenation of an appropriate steroidal intermediate. Among various halogenated steroids, 16 alpha-bromoepiandrosterone was 50 times as potent as dehydroepiandrosterone as an inhibitor of glucose-6-phosphate dehydrogenase.
Assuntos
Desidroepiandrosterona/análogos & derivados , Esteroides Bromados/síntese química , Sulfoglicoesfingolipídeos/síntese química , Animais , Desidroepiandrosterona/síntese química , Eritrócitos/enzimologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Humanos , Camundongos , Esteroides Clorados/síntese química , Esteroides Fluorados/síntese químicaRESUMO
1'-Substituted spiro[fluorene-9,3'-pyrrolidine-2',5'-diones], 1',1''' - (1,4-piperazinediyldimethylene) bis[spiro[fluorene-9,3'-pyrrolidine-2',5'-dione]], and 1'-arylspiro[fluorene-9,3'-pyrrolidines] were synthesized from spiro[fluorene-9,3'-tetrahydrofuran-2',5'-dione]. The rat passive cutaneous anaphylaxis assay showed that one compound possessed slight antiallergic activity. Synthesis of 3-substituted 1-aryl-4-oxospiro[azetidine-2,9'-fluorenes] and 1,1''-p-phenylenebis[4-oxospiro[azetidine-2,9'-fluorenes]] was achieved via the reaction of appropriate N-fluorenylideneanilines with tert-butylcyanoketene and cyclopentamethyleneketene, respectively.
Assuntos
Fluorenos/síntese química , Compostos de Espiro/síntese química , Animais , Fluorenos/farmacologia , Hipersensibilidade/tratamento farmacológico , Ratos , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
3 beta-Alkanesulfonates of dehydroepiandrosterone, 16 alpha-bromodehydroepiandrosterone, epiandrosterone, and 16 alpha-bromoepiandrosterone were prepared in 54-95% yield via the reaction of long chain alkanesulfonyl chlorides with the corresponding dehydroepiandrosterone, and epiandrosterone analogues. These compounds inhibit mouse glucose-6-phosphate dehydrogenase activity.
Assuntos
Androsterona/análogos & derivados , Glucosefosfato Desidrogenase/antagonistas & inibidores , Androsterona/síntese química , Androsterona/farmacologia , Animais , Fenômenos Químicos , Química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pele/enzimologiaRESUMO
Antibiotics containing a beta-lactam ring (e.g. ceftriaxone) display anti-glutamate effects that underlie their efficacy in animal models of central nervous system (CNS) diseases [Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Nature 433:73-77]. We hypothesized that the structurally related beta-lactamase inhibitors (clavulanic acid, tazobactam)--which also contain a beta-lactam ring--will mimic ceftriaxone efficacy in an invertebrate (planarian) assay designed to screen for anti-seizure activity [Rawls SM, Thomas T, Adeola M, Patil T, Raymondi N, Poles A, Loo M, Raffa RB (2009) Pharmacol Biochem Behav 93:363-367]. Glutamate or cocaine administration produced planarian seizure-like activity (pSLA). Glutamate- or cocaine-induced pSLA was inhibited by ceftriaxone, clavulanic acid, or tazobactam, but not by the non-beta-lactam antibiotic vancomyocin. The present findings indicate beta-lactamase inhibitors display efficacy, and mimic ceftriaxone activity, in an invertebrate anti-seizure screen. These results suggest beta-lactamase inhibitors--particularly ones such as clavulanic acid that display enhanced brain penetrability, oral bioavailability, and negligible anti-bacterial activity--might offer an attractive alternative to direct antibiotic therapy for managing CNS diseases caused by increased glutamate transmission and provide a solution to the growing concern that ceftriaxone will be of only limited utility as a CNS-active therapeutic because of its intolerable side effects.
Assuntos
Anticonvulsivantes/farmacologia , Inibidores Enzimáticos/farmacologia , Planárias/efeitos dos fármacos , Convulsões/tratamento farmacológico , Inibidores de beta-Lactamases , Animais , Anticonvulsivantes/uso terapêutico , Modelos Animais de Doenças , Inibidores Enzimáticos/uso terapêutico , Planárias/enzimologia , Convulsões/enzimologia , Convulsões/fisiopatologia , beta-Lactamases/fisiologiaAssuntos
Congêneres do Estradiol/síntese química , Indóis/síntese química , Animais , Densidade Óssea/efeitos dos fármacos , Linhagem Celular , Congêneres do Estradiol/química , Congêneres do Estradiol/metabolismo , Congêneres do Estradiol/farmacologia , Feminino , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Modelos Moleculares , Tamanho do Órgão , Ovariectomia , Ensaio Radioligante , Ratos , Relação Estrutura-Atividade , Transfecção , Útero/efeitos dos fármacosRESUMO
The purpose of this study was to characterize a new chemical entity, desvenlafaxine succinate (DVS). DVS is a novel salt form of the isolated major active metabolite of venlafaxine. Competitive radioligand binding assays were performed using cells expressing either the human serotonin (5-HT) transporter (hSERT) or norepinephrine (NE) transporter (hNET) with K(i) values for DVS of 40.2 +/- 1.6 and 558.4 +/- 121.6 nM, respectively. DVS showed weak binding affinity (62% inhibition at 100 microM) at the human dopamine (DA) transporter. Inhibition of [3H]5-HT or [3H]NE uptake by DVS for the hSERT or hNET produced IC50 values of 47.3 +/- 19.4 and 531.3 +/- 113.0 nM, respectively. DVS (10 microM), examined at a large number of nontransporter targets, showed no significant activity. DVS (30 mg/kg orally) rapidly penetrated the male rat brain and hypothalamus. DVS (30 mg/kg orally) significantly increased extracellular NE levels compared with baseline in the male rat hypothalamus but had no effect on DA levels using microdialysis. To mimic chronic selective serotonin reuptake inhibitor treatment and to block the inhibitory 5-HT(1A) autoreceptors, a 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo hexanecarboxamide maleate salt (WAY-100635) (0.3 mg/kg s.c.), was administered with DVS (30 mg/kg orally). 5-HT increased 78% compared with baseline with no additional increase in NE or DA levels. In conclusion, DVS is a new 5-HT and NE reuptake inhibitor in vitro and in vivo that demonstrates good brain-to-plasma ratios, suggesting utility in a variety of central nervous system-related disorders.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Cicloexanóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Encéfalo/metabolismo , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Cicloexanóis/metabolismo , Cicloexanóis/farmacocinética , Succinato de Desvenlafaxina , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Hipotálamo/metabolismo , Masculino , Microdiálise , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/farmacocinéticaRESUMO
Recent data has suggested that the 5-hydroxytryptamine (5-HT)(1A) receptor is involved in cognitive processing. A novel 5-HT(1A) receptor antagonist, 4-cyano-N-{2R-[4-(2,3-dihydrobenzo[1,4]-dioxin-5-yl)-piperazin-1-yl]-propyl}-N-pyridin-2-yl-benzamide HCl (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacological assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT(1A) receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg s.c.) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg s.c.) of 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT(1A) receptor tolerance or desensitization in a behavioral model indicative of 5-HT(1A) receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg i.m.) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT(1A) agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg p.o.). Learning deficits induced by the glutamatergic antagonist MK-801 [(-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg i.m.) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in Alzheimer's disease.
Assuntos
Acetilcolina/metabolismo , Cognição/efeitos dos fármacos , Dioxanos/farmacologia , Ácido Glutâmico/metabolismo , Hipocampo/efeitos dos fármacos , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Doença de Alzheimer/tratamento farmacológico , Animais , Callithrix , Columbidae , Aprendizagem por Discriminação/efeitos dos fármacos , Feminino , Gânglios Espinais/efeitos dos fármacos , Hipocampo/metabolismo , Macaca mulatta , Masculino , Metoxidimetiltriptaminas/antagonistas & inibidores , Microdiálise , Ratos , Ratos Sprague-Dawley , SaimiriRESUMO
Three degradation products of dezocine were synthesized and tested for possible antinociceptive activity. 13-Amino-5,6,7,8,9,10-hexahydro-5-methyl-5,11-methanobenzocyclodecen+ ++-3-ol demonstrated antinociceptive properties comparable to morphine.