RESUMO
A series of 4-substituted piperazine derivatives bearing a norbornene nucleus have been prepared and their affinity for serotonin 5-HT1A, 5-HT2A and 5-HT2C receptors has been evaluated. Compounds showing the highest affinity have been selected and evaluated on dopaminergic (D1 and D2) and adrenergic (alpha1 and alpha2) receptors. The combination of structural elements (heterocyclic nucleus, oxyalkyl chain and 4-substituted piperazine) known to be critical in order to have affinity on serotonin receptors and the proper selection of substituents led to compounds with higher receptor specificity and affinity. In binding studies, several molecules showed affinity in nanomolar range towards 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate to no affinity for other relevant receptors (D1, D2, alpha1 and alpha2). Compound 2q 4-[2-[4-(3,4-dichlorophenyl)piperazin-1-yl]ethoxy]-4-aza-tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (Ki = 1.13 nM), was the most active and selective derivative for the 5-HT2C receptor with respect to other serotonin, dopaminergic and adrenergic receptors. Moreover, compound 3p showed mixed 5-HT2A/5-HT2C activity with affinity values in nanomolar range.
Assuntos
Norbornanos/síntese química , Norbornanos/farmacologia , Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Serotoninérgicos/síntese química , Serotoninérgicos/farmacologia , Animais , Química Encefálica/efeitos dos fármacos , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2C de Serotonina/química , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Receptores de Dopamina D1/química , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismoRESUMO
Galanthamine is an alkaloid approved for the treatment of Alzheimer's disease. In this paper the syntheses and the anticholinesterase activities of new glucosyl and nitroxy derivatives substituted on position 6 are reported. Compounds 2, 3 and 5 presented a percentage of inhibition of 35.22%, 47.48% and 67.89% respectively.
Assuntos
Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Galantamina/análogos & derivados , Galantamina/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Cromatografia Líquida de Alta Pressão , Galantamina/síntese química , Técnicas In Vitro , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Masculino , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The understanding of the molecular basis of cannabinoid activity has greatly improved since the discovery of CB1 and CB2 receptors. In this paper, the ligand binding processes between the endogenous cannabimimetic ligand, anandamide (AEA), and the cannabinoid receptors from different parts of rat brain were studied by nuclear magnetic resonance spectroscopy. The NMR approach is based on the comparison of selective (R1(SE)) and non-selective (R1(NS)) proton spin-lattice relaxation rates of the ligand in the presence and absence of macromolecular receptors, as well as R1(NS) and R1(SE) temperature dependency analysis. From these studies, the ligand-receptor binding strength was evaluated on the basis of the calculation of the "affinity index". The derivation of the "affinity index" from chemical equilibrium kinetics for all systems allowed the comparison of the ability of anandamide to interact with cannabinoid receptors present in different brain sectors.
Assuntos
Ácidos Araquidônicos/química , Espectroscopia de Ressonância Magnética/métodos , Alcamidas Poli-Insaturadas/química , Receptores de Canabinoides/química , Animais , Ácidos Araquidônicos/farmacologia , Sítios de Ligação , Encéfalo/metabolismo , Endocanabinoides , Ligantes , Espectroscopia de Ressonância Magnética/normas , Masculino , Estrutura Molecular , Alcamidas Poli-Insaturadas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides/efeitos dos fármacos , Padrões de Referência , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
Aseries of oxypropanolamine derivatives of 3,4-dihydro-2H-1,4-benzoxazine were synthesized and evaluated for inotropic, chronotropic and coronary vasodilating activities in the canine heart, affinity to beta(1)-adrenergic receptor in turkey erythrocytes and affinity to the beta(2)-adrenergic receptor in the rat lung. Among these compounds, 4-acetyl-6-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 2.1-fold more potent affinity to the beta(1) receptor than propranolol and 7-(3-tert-butylamino-2-hydroxy)propoxy-N-butyryl-3,4-dihydro-2H-1,4-benzoxazine showed 2.5-fold more potent affinity to the beta(2) receptor and furthermore 4386-fold more potent selectivity to the beta(2) receptor than propranolol. In addition, 4-acetyl-6-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine showed 1.1-fold more potent affinity to the beta(1) receptor than propranolol and also 1147-fold more potent selectivity to the beta(1) receptor. With a few exceptions, negative inotropic and chronotropic actions of these compounds were dependent on the size of the 4-substituent obeying the order: unsubstituted < acetyl < propanoyl < butanoyl, while the benzoyl substituent conferred even stronger negative actions in the 6-oxypropanolamine derivatives. Neither negative inotropic and chronotropic actions related with affinity to beta(1)-adrenoceptor nor coronary vasodilator action related with affinity to beta(2)-adrenoceptor were observed. 4-acetyl-7-[3-(3,4-dimethoxybenzyl)amino-2-hydroxy]propoxy-3,4-dihydro-2H-1,4-benzoxazine exerted potent positive inotropic, chronotropic and coronary vasodilating actions. The inotropic and chronotropic actions of the latter compound may be attributed to the release of intrinsic catecholamines, as concluded by the absence of beta(1)-adrenoceptor affinity and disappearance of activity in the presence of a beta-blocker.
RESUMO
The synthesis of a new series of sesamol derivatives with beta-adrenergic blocking activity is described. The affinity and selectivity of these compounds for beta 1- and beta 2-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the beta 2-receptors of rat lung membranes and two of them provide interesting selectivity.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1 , Antagonistas de Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/síntese química , Antagonistas Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Pulmão/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Propanolaminas/metabolismo , Propanolaminas/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Espectrofotometria InfravermelhoRESUMO
A large series of 2-aryl(heteroaryl)-2,5-dihydropyrazolo[4,3-c]quinolin- 3-(3H)-ones, carrying appropriate substituents at the quinoline and N2-phenyl rings, were prepared and tested as central benzodiazepine receptor ligands. Results from structure-affinity relationship studies were in full agreement with previously proposed pharmacophore models and, in addition, quantitative structure-activity analysis gave further significant insight into the main molecular determinants of high benzodiazepine receptor affinity. The intrinsic activity of some active ligands was also determined and preliminary discussed.
Assuntos
Agonistas GABAérgicos/química , Antagonistas GABAérgicos/química , Pirazóis/química , Quinolonas/química , Receptores de GABA-A/química , Animais , Ansiolíticos/metabolismo , Córtex Cerebral/metabolismo , Técnicas de Cultura , Flunitrazepam/metabolismo , Agonistas GABAérgicos/metabolismo , Antagonistas GABAérgicos/metabolismo , Ligantes , Espectroscopia de Ressonância Magnética , Masculino , Pirazóis/metabolismo , Quinolonas/metabolismo , Ratos , Ratos Sprague-Dawley , Espectrofotometria Infravermelho , Relação Estrutura-AtividadeRESUMO
A number of pyruvic acid and methylpyruvate alpha-(N)-heterocyclic hydrazones has been synthesized. Bis-heterocyclic hydrazones were obtained from reaction with pyruvic carboxaldehyde. Some complexes of Ni(II) were prepared and characterized as neutral complexes. All these compounds have been evaluated for cytotoxicity against P388 and HL-60 leukemia.
Assuntos
Antineoplásicos/síntese química , Quelantes/síntese química , Hidrazonas/síntese química , Animais , Antineoplásicos/farmacologia , Quelantes/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HL-60 , Humanos , Hidrazonas/farmacologia , Leucemia P388/tratamento farmacológico , Ligantes , Espectroscopia de Ressonância Magnética , Camundongos , Espectrofotometria Infravermelho , Células Tumorais CultivadasRESUMO
Several 1-[quinolyl(4)]-1,2,3-triazoles were synthesized by 1,3-dipolar cycloaddition of 4-azidoquinolines with activated methylene compounds. The synthesized compounds, tested for antiinflammatory and analgesic activities, resulted moderately active as antiinflammatories, but with a very interesting analgesic activity, sometimes higher than that of indomethacin, used as reference drug. Some of the triazole derivatives were evaluated also as antimicrobial, but none of them exhibited activity.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Triazóis/síntese química , Analgésicos/farmacologia , Animais , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Masculino , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
The synthesis of new 1-[quinolyl(4)]-1,2,3-triazoles is reported. These have been obtained by reacting 4-azidoquinolines with ethyl p-nitrobenzoylacetate. The synthesized compounds, tested for antiinflammatory and analgesic activities, results moderately active as antiinflammatories, but with a very interesting analgesic activity, sometimes higher than that of indomethacin, used as reference drug.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Triazóis/síntese química , Analgésicos/efeitos adversos , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Wistar , Espectrofotometria Ultravioleta , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Triazóis/efeitos adversos , Triazóis/farmacologiaRESUMO
Two new series of 2-arylpyrazolo[4,3-c]quinolin-3-ones (6,8-difluoro- and 7,9-dichloro-derivatives) have been synthesized and tested for their ability to displace [3H]flunitrazepam from rat brain membranes. Several compounds possess comparable and sometimes higher affinity for central benzodiazepine receptors than that of diazepam. Some selected compounds were also tested in vivo in the anti-pentylenetetrazol test; some anticonvulsant activity resulted for the 6,8-difluoroderivatives only.
Assuntos
Anticonvulsivantes/síntese química , Pirazóis/síntese química , Quinolinas/síntese química , Receptores de GABA-A/metabolismo , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Sítios de Ligação , Ligação Competitiva , Feminino , Flunitrazepam/metabolismo , Camundongos , Pentilenotetrazol/antagonistas & inibidores , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Receptores de GABA-A/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The synthesis of new halogenated series of 4-anilinoquinoline-3-carboxylic acids, N-[3-carboxyquinolyl(4)]anthranilic acids and their corresponding esters is reported. These have been obtained by reacting 4-chloro-3-carbethoxy-quinolines with variously substituted anilines and methyl anthranilate respectively. The synthesized compounds were tested for antiinflammatory and analgesic activities; some of them showed a good analgesic activity, sometimes higher than that of indomethacin, used as reference drug.
Assuntos
Compostos de Anilina/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Quinolinas/síntese química , ortoaminobenzoatos/síntese química , Compostos de Anilina/farmacologia , Compostos de Anilina/toxicidade , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Carragenina , Fenômenos Químicos , Físico-Química , Edema/induzido quimicamente , Edema/prevenção & controle , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Medição da Dor/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Quinolinas/farmacologia , Quinolinas/toxicidade , Coelhos , Ratos , Ratos Wistar , Úlcera Gástrica/induzido quimicamente , ortoaminobenzoatos/farmacologia , ortoaminobenzoatos/toxicidadeRESUMO
Synthesis and pharmacological evaluation of a series of 4-quinolylazide derivatives are reported. These were screened against P388 lymphocitic leukemia in mice, but they resulted inactive. All the compounds were also tested for their antimicrobial activity against gram-positive, gram-negative strains and fungi; only three derivatives exhibited poor activity.
Assuntos
Anti-Infecciosos/síntese química , Antineoplásicos/síntese química , Azidas/síntese química , Quinolinas/síntese química , Animais , Antibacterianos , Anti-Infecciosos/farmacologia , Antineoplásicos/farmacologia , Azidas/farmacologia , Bactérias/efeitos dos fármacos , Fenômenos Químicos , Físico-Química , Fungos/efeitos dos fármacos , Leucemia P388/tratamento farmacológico , Camundongos , Camundongos Endogâmicos , Testes de Sensibilidade Microbiana , Quinolinas/farmacologiaRESUMO
A series of 2-arylpyrazolo[4,3-c] quinolin-3-one derivatives, bearing different substituents in the two aromatic rings, were prepared and tested for their ability to displace [3H] flunitrazepam from rat brain membranes. Some compounds have shown an affinity for receptors comparable and sometimes higher than that of CGS series.
Assuntos
Antagonistas de Receptores de GABA-A , Pirazóis/síntese química , Quinolinas/síntese química , Animais , Ligação Competitiva/efeitos dos fármacos , Encéfalo/metabolismo , Flunitrazepam/metabolismo , Técnicas In Vitro , Pirazóis/farmacologia , Quinolinas/farmacologia , Ratos , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
New 4-anilinoquinoline-3-carboxylic acids, N-[3-carboxyquinolyl (4)]anthranilic acids and their corresponding esters were synthetized by reacting 4-chloro-3-carbethoxyquinolines with substituted anilines and methyl anthranilate respectively. All the compounds were tested for antiinflammatory and analgesic activities. Some derivatives showed a significant antiinflammatory activity comparable to that of indomethacin.
Assuntos
Analgésicos , Anti-Inflamatórios não Esteroides , Quinolinas/farmacologia , Animais , Carragenina , Fenômenos Químicos , Química , Edema/induzido quimicamente , Edema/tratamento farmacológico , Masculino , Dor/tratamento farmacológico , Dor/fisiopatologia , Quinolinas/síntese química , Ratos , Ratos Endogâmicos , Tempo de Reação/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacosRESUMO
To investigate the hypothesis that the rate of fatigue development is not influenced by the absolute duration of contraction (train duration) and relaxation (off-phase of duty cycle) at constant duty cycle, strips of the diaphragm from 36 male adult rats (mean +/- SD wt 152 +/- 21 g) were stimulated directly for periods of 180, 250, and 320 ms at a constant duty cycle of 50%. The frequency of stimulation was adjusted to produce 40% of maximal tetanic tension at supramaximal voltages. After 30 min of stimulation, analysis of twitch characteristics between control and experimental groups indicated a prolongation of contraction time of 9% (P less than 0.05), an increase in relaxation time of 75% (P less than 0.05), and a decrease in twitch tension by 78% (P less than 0.05). Similarly, reductions (P less than 0.05) in isometric force output at high stimulation frequency (100 Hz) of 58% and at low frequency (20 Hz) of 67% were also noted. These changes were accompanied by an approximately 60% reduction in the maximal velocity of shortening. No difference was observed for any of the mechanical measures between experimental conditions. After 30-min stimulation, decreases of between 43 and 46% were noted for ATP (P less than 0.05) and increases of between three- and fourfold noted for IMP (P less than 0.05). No changes were found for either ADP or AMP. Total adenine nucleotide concentrations declined (P less than 0.05) an average of 24%. As with the mechanical data, no differences were found between the different stimulation conditions. It is concluded that for the conditions studied, fatigue mechanisms become manifest early in the stimulation period and are only minimally altered by the duration of specific contractions provided the relaxation period is of equal duration.
Assuntos
Diafragma/fisiologia , Contração Muscular , Animais , Diafragma/metabolismo , Estimulação Elétrica , Técnicas In Vitro , Masculino , Relaxamento Muscular , Ratos , Ratos EndogâmicosRESUMO
Tridentate chelating agents, as potential antitumor agents, were prepared by condensing 2-quinolylhydrazines, 2-pyridylhydrazine and 2-benzothiazolylhydrazine with pyridine-2-aldehyde, 6-methylpyridine-2-aldehyde, 2-acetylpyridine and 2-benzoylpyridine. All compounds were tested against Lymphocytic leukemia P388. The active pyridine-2-aldehyde-4-methyl-2-quinolylhydrazone [1-(4'-methyl-2'-quinolyl)-3-(2'-pyridyl)-1,2-diaza-2-propene] (I d) was also tested against other experimental tumors and proved inactive.