RESUMO
Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT2) and α1-adrenergic receptor antagonist and a serotonin reuptake inhibitor. Our research aimed to develop a new method for the synthesis of trazodone and its derivatives. In the known methods of the synthesis of trazodone and its derivatives, organic and toxic solvents are used, and the synthesis time varies from several to several dozen hours. Our research shows that trazodone and its derivatives can be successfully obtained in the presence of potassium carbonate as a reaction medium in the microwave field in a few minutes. As a result of the research work, 17 derivatives of trazodone were obtained, including compounds that exhibit the characteristics of 5-HT1A receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT1A and 5-HT2A receptors between ligand 10a (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) (5-HT1A Ki = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand 10a to 5-HT2AR, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT1A receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.
Assuntos
Antagonistas Adrenérgicos/química , Antidepressivos/química , Técnicas de Química Sintética , Receptor 5-HT1A de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/química , Trazodona/análogos & derivados , Antagonistas Adrenérgicos/síntese química , Animais , Antidepressivos/síntese química , Sítios de Ligação , Carbonatos/química , Cristalografia por Raios X , Humanos , Ligantes , Micro-Ondas , Simulação de Acoplamento Molecular , Potássio/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Receptor 5-HT2A de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Homologia Estrutural de Proteína , Relação Estrutura-Atividade , Fatores de Tempo , Trazodona/síntese químicaRESUMO
A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for α1-(compound 2 and 8), ß-(compounds 1, 3, 4, 7), α1/ß-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti-aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives.
Assuntos
Antagonistas Adrenérgicos/síntese química , Desenho de Fármacos , Xantonas/química , Antagonistas Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Concentração Inibidora 50 , Masculino , Agregação Plaquetária/efeitos dos fármacos , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa/química , Receptores Adrenérgicos alfa/metabolismo , Receptores Adrenérgicos beta/química , Receptores Adrenérgicos beta/metabolismo , Relação Estrutura-Atividade , Verapamil/química , Xantonas/metabolismo , Xantonas/farmacologiaRESUMO
ß-adrenergic receptors (ß-ARs) are broadly distributed in various tissues and regulate a panel of important physiological functions and disease states including cancer. Above all, ß3-adrenergic receptor (ß3-AR) plays a significant role in regulating lipolysis and thermogenesis in adipose tissue. In this study, we designed and synthesized a series of novel L-748,337 derivatives as selective human ß3-AR antagonists. Among all the tested L-748,337 analogs, compound 23d was found to display 23-fold more potent ß3-AR antagonist activity (EC50â¯=â¯0.5117â¯nM) than L-748,337 (EC50â¯=â¯11.91â¯nM). In vivo, compound 23d could alleviate weight loss and inhibit tumor growth in C26 tumor cachexia animal model.
Assuntos
Antagonistas Adrenérgicos/farmacologia , Desenho de Fármacos , Lipólise/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 3/metabolismo , Células 3T3-L1 , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/química , Animais , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Neoplasias/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Propanolaminas/síntese química , Propanolaminas/química , Relação Estrutura-AtividadeRESUMO
Subtype-selective α1-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α1-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α1B-AR (pA2 7.13) with a poor selectivity for α1A and α1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α1D subtype (pA2 7.06) and excellent selectivity for α1D over α1B (α1D/α1B ratio=79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α1 receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α1D-selective antagonists.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Carbazóis/farmacologia , Desenho de Fármacos , Piperazinas/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas Adrenérgicos/química , Carbazóis/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Piperazinas/química , Relação Estrutura-AtividadeRESUMO
α1-adrenoceptor (α1-AR) subtype-selective ligands lacking off-target affinity for the 5-HT(1A) receptor (5-HT(1A)-R) will provide therapeutic benefits in the treatment of urogenital conditions such as benign prostatic hyperplasia. In this study we determined the affinity of 4-aminoquinoline and eleven homobivalent 4-aminoquinoline ligands (diquinolines) with alkane linkers of 2-12 atoms (C2-C12) for α(1A), α(1B) and α(1D)-ARs and the 5-HT(1A)-R. These ligands are α(1A)-AR antagonists with nanomolar affinity for α(1A) and α(1B)-ARs. They display linker-length dependent selectivity for α(1A/B)-ARs over α(1D)-AR and the 5-HT(1A)-R. The C2 diquinoline has the highest affinity for α1A-AR (pKi 7.60±0.26) and greater than 30-fold and 600-fold selectivity for α(1A)-AR over α(1D)-AR and 5-HT(1A)-R respectively. A decrease in affinity for α1-ARs is observed as the linker length increases, reaching a nadir at 5 (α(1A/1B)-ARs) or 6 (α(1D)-AR) atoms; after which affinity increases as the linker is lengthened, peaking at 9 (α(1A/1B/1D)-ARs) or 8 (5-HT(1A)-R) atoms. Docking studies suggest that 4-aminoquinoline and C2 bind within the orthosteric binding site, while for C9 one end is situated within the orthosteric binding pocket, while the other 4-aminoquinoline moiety interacts with the extracellular surface. The limited α(1D)-AR and 5-HT(1A)-R affinity of these compounds makes them promising leads for future drug development of α(1A)-AR selective ligands without α(1D)-AR and the 5-HT(1A)-R off-target activity.
Assuntos
Antagonistas Adrenérgicos/metabolismo , Aminoquinolinas/metabolismo , Membrana Celular/química , Receptor 5-HT1A de Serotonina/química , Receptores Adrenérgicos alfa 1/química , Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Células COS , Fracionamento Celular , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Chlorocebus aethiops , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , TransfecçãoRESUMO
The synthesis of (2R,S)-1-(6-methoxy-4-(methoxymethyl)-1H-indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2R,S)-1-(4-methoxy-6-(methoxymethyl)-1H-indol-5-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol is described. The compounds were tested for electrographic, antiarrhythmic, hypotensive, and spasmolytic activity, as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptor binding affinity.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Propanolaminas/síntese química , Propanolaminas/uso terapêutico , Antagonistas Adrenérgicos/química , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas de Receptores Adrenérgicos alfa 2 , Antagonistas de Receptores Adrenérgicos beta 1 , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/química , Antiarrítmicos/uso terapêutico , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Pressão Sanguínea/efeitos dos fármacos , Eletrocardiografia , Epinefrina/toxicidade , Íleo/efeitos dos fármacos , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Propanolaminas/química , Coelhos , RatosRESUMO
The synthesis of (2RS)-1-(5-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and (2RS)-1-(7-methoxy-1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and its enantiomers, analogs of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol ((RS)-9) is described. Compounds were tested for electrographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptors binding affinities. The antagonist potency of the new compounds was compared with carvedilol and (RS)-9.
Assuntos
2-Propanol/síntese química , Antagonistas Adrenérgicos/síntese química , Anti-Hipertensivos/síntese química , Carbazóis/síntese química , Propanolaminas/síntese química , 2-Propanol/química , 2-Propanol/farmacologia , Antagonistas Adrenérgicos/química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Carvedilol , Íleo/efeitos dos fármacos , Masculino , Estrutura Molecular , Propanolaminas/química , Propanolaminas/farmacologia , Coelhos , Ratos , Ratos Wistar , EstereoisomerismoRESUMO
A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha(1)- and alpha(2)-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the alpha(1)-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK(i)=7.28. The highest affinity for the alpha(2)-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK(i)=6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for alpha(1B)- and alpha(1D)-AR, which gave pA(2) alpha(1B)=6.55 and pA(2) alpha(1D)=7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50) value was 1.1mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5-5.0mg/kg (i.v.) and their hypotensive effects lasted for longer than 1h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both alpha(1)- and alpha(2)-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure-activity relationship, a preliminary molecular modeling study was undertaken.
Assuntos
Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/uso terapêutico , Antiarrítmicos/química , Antiarrítmicos/uso terapêutico , Anti-Hipertensivos/química , Anti-Hipertensivos/uso terapêutico , Piperazinas/química , Piperazinas/uso terapêutico , Pirrolidinonas/química , Pirrolidinonas/uso terapêutico , Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/tratamento farmacológico , Pressão Sanguínea/efeitos dos fármacos , Cobaias , Masculino , Modelos Moleculares , Piperazinas/síntese química , Piperazinas/farmacologia , Ligação Proteica , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis of (2RS)-1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino}propan-2-ol ((RS)-9) and its enantiomers has been described and tested for electrocardiographic, antiarrhythmic, hypotensive and spasmolytic activities as well as for alpha(1)-, alpha(2)- and beta(1)-adrenoceptors' binding affinities. All compounds significantly decrease systolic and diastolic blood pressure, and possess antiarrhythmic activity and affinity to alpha(1)-, alpha(2)- and beta(1)-adrenoceptors. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic but not spasmolytic properties.
Assuntos
Antagonistas Adrenérgicos/síntese química , Indóis/síntese química , Propanolaminas/síntese química , Propanóis/síntese química , Receptores Adrenérgicos/metabolismo , 2-Propanol , Antagonistas Adrenérgicos/farmacologia , Animais , Antiarrítmicos/síntese química , Arritmias Cardíacas/tratamento farmacológico , Eletrocardiografia , Hipotensão/tratamento farmacológico , Indóis/farmacologia , Parassimpatolíticos/síntese química , Propanolaminas/farmacologia , Propanóis/farmacologia , Coelhos , Ratos , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Espasmo/tratamento farmacológico , EstereoisomerismoRESUMO
We performed the asymmetric synthesis of four enantiopure benzo[d] isothiazo-3-or 5-yloxypropanolamine derivatives, previously described as competitive antagonists at beta-adrenoceptors. The chemical characterization of each enantiomer was accomplished by (1)H NMR and HPLC/DAD/CD. The direct chromatographic separation of the enantiomers via chiral HPLC was investigated. The best resolutions were achieved using cellulose tris (3,5-dimethylphenyl carbamate) (Chiralcel OD-H) and amylose tris (3,5-dimethylphenyl carbamate) (Chiralpak AD). The enantiomers obtained had enantiomeric purities suitable for biological assays. Tested in isolated rat cardiac and intestinal tissues to evaluate their effects at beta(1)- and beta(3)-adrenoceptors, the (S)-enantiomers revealed a higher degree of antagonism than (R)-enantiomers at both subtypes, even though their activity was greater at the cardiac beta(1)-subtype. The potent and cardiospecific antagonistic effect exerted by the compounds tested suggests that the benzisothiazole moiety could be an interesting scaffold for discovering new chiral beta-blocking drugs.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Propanolaminas/síntese química , Propanolaminas/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/isolamento & purificação , Animais , Cromatografia , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Íleo/efeitos dos fármacos , Íleo/metabolismo , Masculino , Propanolaminas/química , Propanolaminas/isolamento & purificação , Ratos , Estereoisomerismo , Especificidade por Substrato , Tiazóis/química , Tiazóis/isolamento & purificaçãoRESUMO
Eight derivatives of general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate were synthesized and tested for electrocardiographic, antiarrhythmic, vasorelaxing and antihypertensive activity as well as for in-vitro nitric oxide (NO) releasing ability. Compound 8b 2-(2-(4-(3-(5-benzyliden-4-oxo-2-(phenylimino)thiazolidin-3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate, was the most potent in this series. The pharmacological results suggested that the antiarrhythmic effects of these compounds were related to their adrenolytic properties which are believed to be due to the presence of the 5-(substituted)methylen-2-(phenylimino)thiazolidin-4-one moiety with less bulky, electron donating substituent on the phenyl ring at 5th position of the thiazolidin-4-one. In conclusion, most of the synthesized compounds were significantly potent as antiarrhythmic and antihypertensive; this might be due to the presence of different pharmacopores which might act at different locations with different mode of action. Further insights of the same can be obtained by doing investigation at receptor level. The potency of compounds 8a-8h were promising enough to continue further experiments.
Assuntos
Anti-Hipertensivos/síntese química , Antagonistas Adrenérgicos/síntese química , Animais , Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/farmacologia , Aorta , Pressão Sanguínea/efeitos dos fármacos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
An alpha1a-adrenoceptor-selective antagonist has the potential to be a new benign prostatic hyperplasia drug with reduced side-effects. Modification of the non-selective antagonist BE2254 led to the development of a series of tetralin analogs. Evaluation of these compounds in cloned human alpha1-adrenoceptors resulted in the discovery of an analog that showed selectivity toward the human alpha1a-adrenergic receptor subtype. The compound also showed moderate potency to block human prostate muscle contraction.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/síntese química , Antagonistas Adrenérgicos alfa/farmacologia , Desenho de Fármacos , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos alfa/química , Humanos , Masculino , Estrutura Molecular , Próstata/efeitos dos fármacos , Próstata/fisiologia , Hiperplasia Prostática/tratamento farmacológico , Especificidade por Substrato , Tetra-Hidronaftalenos/químicaRESUMO
In our previous paper we have described the synthesis of a series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles, as novel dual 5-HT reuptake inhibitors and alpha2-adrenoceptor antagonists. That investigation led to the identification of the cinnamyl fragment as the most suitable moiety for combined activity. This paper outlines a further optimisation programme, focused on the exploration of the aromatic ring present on the cinnamyl moiety of compounds 1, 2 and 3.
Assuntos
Antagonistas Adrenérgicos/síntese química , Isoxazóis/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antagonistas Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2 , Cinamatos/química , Humanos , Concentração Inibidora 50 , Isoxazóis/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
(R)- and (S)-1-chloro-3-(1-naphthyloxy)-2-propanol are intermediates in the synthesis of beta-adrenergic blocking agents and antihypertensive drugs such as propranolol and nadoxolol. Herein, improvement in the preparation of racemic 1-chloro-3-(1-naphthyloxy)-2-propanol generated from 1-naphthol and epichlorohydrin are reported. In addition, kinetic resolution studies have been conducted to obtain both (R) and (S)-1-chloro-3-(1-naphthyloxy)-2-propanol. These compounds were obtained in highly optically pure form by the stereoselective hydrolysis of its acyl derivatives using whole cell preparations containing enzymes from native sources. The results were compared with those obtained using commercial lipases.
Assuntos
Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/síntese química , Cloridrinas/química , Naftalenos/química , Acilação , Candida/enzimologia , Hidrolases/metabolismo , Cinética , Lipase/metabolismo , Mucor/enzimologia , EstereoisomerismoRESUMO
Antagonists of the alpha(1)-adrenergic receptors (alpha(1)-ARs) are useful for the treatment of benign prostatic hyperplasia. A series of potent and subtype-selective alpha(1a)-AR antagonists has been synthesized, displaying in vitro binding affinity in the low the nanomolar range.
Assuntos
Antagonistas Adrenérgicos/síntese química , Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Isoxazóis , Piperazinas/síntese química , Piperazinas/farmacologia , Ligação Proteica , Receptores Adrenérgicos alfa 1 , Sensibilidade e Especificidade , Relação Estrutura-AtividadeRESUMO
A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated alpha-/beta-adrenoceptor blocking activities created a new family of calcium entry and the third generation beta-adrenoceptor blockers. Optimizing this research to obtain more potent alpha-/beta-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and alpha-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac effects of all the compounds 1a-1j resulted from calcium entry and beta-adrenoceptor blocking, which attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 1b as candidate compound for further pharmacological and pre-clinical evaluation studies.
Assuntos
Bloqueadores dos Canais de Cálcio/síntese química , Di-Hidropiridinas/farmacologia , Antagonistas Adrenérgicos/síntese química , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/farmacologia , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Vias de Administração de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Fenilpropanolamina/química , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
Palladium-catalyzed condensation of benzene-1,2-diol with various propargylic carbonates afforded regio- and stereoselectively 2,3-dihydro-2-ylidene-1,4-benzodioxins. The reaction is suggested to proceed by the formation of a (sigma-allenyl)palladium complex, followed by the intermolecular attack of the phenoxide ion on this complex to generate a new (sigma-allyl)palladium complex in equilibrium with the corresponding (eta(3)-allyl)palladium complex. Intramolecular attack of the phenoxide ion afforded the corresponding benzodioxan compound. This last attack occurs predominantly at the more electrophilic end of the (eta(3)-allyl)palladium intermediate. The Z- or E-stereochemistry of the products was established by (1)H NMR and proton NOE measurements and also by X-ray analysis on an example. The Z-stereochemistry generally observed is in agreement with the formation of this (eta(3)-allyl)palladium intermediate. However, in the case of tertiary propargylic carbonates, the E-stereochemistry generally observed could be explained by an intramolecular attack of the phenoxide ion on the intermediate (sigma-allyl)palladium complex, in slow equilibrium with the (eta(3)-allyl)palladium complex.
Assuntos
Antagonistas Adrenérgicos/síntese química , Propanolaminas/química , Propanolaminas/síntese química , Antagonistas Adrenérgicos/química , Catálise , Inibidores Enzimáticos/síntese química , Inibidores de Lipoxigenase , Estrutura Molecular , Paládio/química , EstereoisomerismoRESUMO
A series of analogs of SNAP 5150 containing heteroatoms at C2 or C6 positions is described. Herein, we report that the presence of alkyl substituted heteroatoms at the C2(6)-positions of the dihydropyridine are well tolerated. In addition, 15 inhibited the phenylephrine induced contraction of dog prostate tissue with a Kb of 1.5 nM and showed a Kb (DBP, dogs, microg/kg)/Kb (IUP, dogs, microg/kg) ratio of 14.8/2.5.
Assuntos
Antagonistas Adrenérgicos/síntese química , Di-Hidropiridinas/síntese química , Antagonistas Adrenérgicos/farmacologia , Animais , Canais de Cálcio/metabolismo , Di-Hidropiridinas/farmacologia , Cães , Humanos , Masculino , Estrutura Molecular , Fenilefrina/farmacologia , Próstata/efeitos dos fármacos , Hiperplasia Prostática/tratamento farmacológico , Ligação Proteica , Ratos , EstereoisomerismoRESUMO
A still unknown tricyclic heterocyclic system (5) was synthesized from 6-hydroxy-2-methylpyridazin-3-one and its structure identified as 2,8-dichloro-6-methylpyrrolo[1,2-b:3,4-d']dipyridazin-5(6H)- one by spectroscopic investigations. Selective condensation of 5 with 2-[4-(2-substituted-phenyl)piperazin-1-yl]ethylamine gave the 2-arylpiperazinylethylamino-8-chloro derivatives 6a-c, which were investigated in binding studies toward the three alpha1-adrenergic and 5-HT1A-serotonergic receptor subtypes. They displayed high potency on all the assays and some selectivity for alpha1a and alpha1d subtypes.
Assuntos
Antagonistas Adrenérgicos/síntese química , Piridazinas/síntese química , Pirróis/síntese química , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Antagonistas Adrenérgicos/química , Antagonistas Adrenérgicos/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Células CHO , Cricetinae , Humanos , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Piridazinas/química , Piridazinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Ensaio Radioligante , Receptores Adrenérgicos alfa 1/biossíntese , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Relação Estrutura-Atividade , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 x 12 matrix, were combined to form 96 individual compounds.