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1.
Acta Pol Pharm ; 58(2): 79-86, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11501794

RESUMO

The conformational of selected 1-(2-pyrimidinyl)piperazine derivatives with high sedative-hypnotic activity was analysed and the model bioactive conformations were suggested. Subsequently, the pharmacophores of analysed compounds were designed. It was suggested that the pharmacophore of bioactive derivatives should be composed of 11 features that characterise the binding model of pyrimidinylpiperazine ligands to the binding site at the hypothetic receptor. This 11 feature pharmacophore was compared to three other pharmacophores designed for the selected anxiolytics (benzodiazepines and buspirone analogues) and the sedative-hypnotic agents (benzodiazepines and barbiturates). Several substantial differences between the pharmacophores were found: the number of pharmacophoric features and their distribution in 3-D space were unique for selected groups of compounds that exhibit sedative-hypnotic or anxiolytic activity.


Assuntos
Hipnóticos e Sedativos/química , Piperazinas/química , Hipnóticos e Sedativos/farmacologia , Modelos Moleculares , Conformação Molecular , Piperazinas/farmacologia , Relação Estrutura-Atividade
2.
Bioorg Med Chem ; 9(4): 881-95, 2001 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11354671

RESUMO

Three-dimensional (3-D) models of the human serotonin 5-HT1A and 5-HT2A receptors were constructed, energy refined, and used to study the interactions with a series of buspirone analogues. For both receptors, the calculations showed that the main interactions of the ligand imide moieties were with amino acids in transmembrane helix (TMH) 2 and 7, while the main interactions of the ligand aromatic moieties were with amino acids in TMH5, 6 and 7. Differences in binding site architecture in the region of highly conserved serine and tyrosine residues in TMH7 gave slightly different binding modes of the buspirone analogues at the 5-HT1A and 5-HT2A receptors. Molecular dynamics simulations of receptor-ligand interactions indicated that the buspirone analogues did not alter the interhelical hydrogen bonding patterns upon binding to the 5-HT2A receptor, while interhelical hydrogen bonds were broken and others were formed upon ligand binding to the 5-HT1A receptor. The ligand-induced changes in interhelical hydrogen bonding patterns of the 5-HT1A receptor were followed by rigid body movements of TMH2, 4 and 6 relative to each other and to the other TMHs, which may reflect the structural conversion into an active receptor structure.


Assuntos
Buspirona/análogos & derivados , Buspirona/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Buspirona/química , Ligantes , Modelos Moleculares , Conformação Proteica , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/química , Receptores 5-HT1 de Serotonina
3.
Chirality ; 13(3): 148-52, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11270324

RESUMO

The behavior of a series of 3-amino-2-oxazolidinone derivatives with a potential hypnotic activity on achiral (octadecylsilane) and chiral (cellulose tris(4-methylbenzoate)) stationary phases was examined. The compounds differed in the composition of a substituted aromatic ring containing different substituents in different positions. It was possible to resolve all the compounds with selectivity 1.11 < or = alpha < or = 2.74. The enantiodifferentiating power of substituents was correlated to their electron donating ability and position in the aromatic ring.


Assuntos
Benzoatos/química , Celulose/química , Oxazolidinonas/química , Psicotrópicos/química , Celulose/análogos & derivados , Cromatografia Líquida de Alta Pressão , Cinética , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Oxazolidinonas/farmacologia , Psicotrópicos/farmacologia , Estereoisomerismo , Especificidade por Substrato
4.
Acta Pol Pharm ; 58(5): 357-65, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11876443

RESUMO

Preparation of some new 1,4-substituted 2-methylpiperazine derivatives is reported. The influence of structural modifications on their affinity to 5-HT(1A) receptors is discussed. Compounds were synthesised by the reaction of 2-methylpiperazine with 2-chloropyrimidine or 2-chloroquinoline followed by condensation with 1,4 dibromobutane. The resulting quaternary ammonium salts after the reaction with an imide gave the respective final products.


Assuntos
Piperazinas/síntese química , Receptores de Serotonina/metabolismo , Serotoninérgicos/síntese química , Animais , Ligação Competitiva , Hipocampo/química , Hipocampo/metabolismo , Técnicas In Vitro , Ligantes , Piperazinas/metabolismo , Ensaio Radioligante , Ratos , Receptores 5-HT1 de Serotonina , Serotoninérgicos/metabolismo
5.
J Comput Aided Mol Des ; 15(11): 1005-23, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11989622

RESUMO

In the present study experimentally determined ligand selectivity of three methylated buspirone analogues (denoted as MM2, MM5 and P55) towards 5-HT1A and 5-HT2A serotonin receptors was theoretically investigated on a molecular level. The relationships between the ligand structure and 5-HT1A and 5-HT2A receptor affinities were studied and the results were found to be in agreement with the available site-directed mutagenesis and binding affinity data. Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT1A/5-HT2A, each time in a different orientation. Present results were compared with our previous theoretical results, obtained for buspirone and its non-methylated analogues. It was found that due to the presence of the methyl group in the piperazine ring the ligand position alters and the structure of the ligand-receptor complex is modified. Further, the positions of derivatives with pyrimidinyl aromatic moiety and quinolinyl moiety are significantly different at the 5-HT2A receptor. Thus, methylation of such derivatives alters the 3D structures of ligand-receptor complexes in different ways. The ligand-induced changes of the receptor structures were also analysed. The obtained results suggest, that helical domains of both receptors have different dynamical behaviour. Moreover, both location and topography of putative binding sites for buspirone analogues are different at 5-HT1A and 5-HT2A receptors.


Assuntos
Buspirona/análogos & derivados , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/metabolismo , Sítios de Ligação/genética , Buspirona/química , Buspirona/metabolismo , Simulação por Computador , Desenho de Fármacos , Humanos , Técnicas In Vitro , Ligantes , Substâncias Macromoleculares , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação Proteica , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/genética , Receptores 5-HT1 de Serotonina , Termodinâmica
6.
J Med Chem ; 43(20): 3671-6, 2000 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-11020281

RESUMO

A series of alpha-asarone isomers was synthesized and investigated for their hypolipidemic and antiplatelet activity. Considering the hypolipidemic activity in rats at a dose of 80 mg/kg/day, some isomers were more potent than clofibrate at 150 mg/kg. Compound 3 was one of the most active agents elevating the HDL cholesterol level by 56% and lowering the LDL cholesterol level by 46.8% in rats after 7 days of administration. The activities of the platelet aggregation test in vitro were significant but lower than those of the reference substances (indomethacine and acetylsalicylic acid). In the pulmonary thromboembolic in vivo test in mice, two compounds (alpha-asarone (6) and compound 4) produced significant antithrombotic effects at 100 mg/kg, namely 44% and 52% protection against lung microembolia, respectively. alpha-Asarone derivatives form a new group of potential hypolipidemic and/or antithrombotic agents. The compounds 3, 4, and 6 may serve as lead substances whose structural modifications may result in original drugs.


Assuntos
Anisóis/síntese química , Fibrinolíticos/síntese química , Hipolipemiantes/síntese química , Derivados de Alilbenzenos , Animais , Anisóis/química , Anisóis/farmacologia , Fibrinolíticos/química , Fibrinolíticos/farmacologia , Humanos , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Técnicas In Vitro , Pulmão/irrigação sanguínea , Masculino , Camundongos , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Tromboembolia/prevenção & controle
7.
Farmaco ; 55(3): 191-3, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10919079

RESUMO

In the present paper the general structure and pharmacophore of some 5-HT1A receptor ligands are described. For several compounds (approximately 15) the intrinsic activity in lower lip retraction (postsynaptic, rat) and hypothermia (presynaptic, mice) tests was determined. For the identified functional presynaptic agonists and antagonists the influence on the brain serotonin level was examined. No direct correlation between the functional intrinsic activity and the influence on the level was observed. Molecular modelling revealed the possibility of the existence of different binding sites for different examined compounds.


Assuntos
Receptores de Serotonina/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Ligantes , Conformação Molecular , Ratos , Receptores 5-HT1 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologia
8.
Acta Pol Pharm ; 57 Suppl: 40-5, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11293260

RESUMO

In present study the structure-selectivity relationship of buspirone and six of its analogues towards 5-HT1A and 5-HT2A serotonin receptors was investigated on molecular level. Molecular mechanics energy minimisation and advanced molecular dynamics (MD) simulations allowed us to perform a dynamic structural analysis of transmembrane helical domains of the human 5-HT1A and 5-HT2A receptors and investigate the ligand-induced changes of the entire structure of the ligand-receptor complex. The obtained results suggest, that helical and extracellular domains of both receptors have different topography of the putative binding sites and also different dynamical behaviour. The results of this study are consistent with experimental site-directed mutagenesis data and binding affinities of examined ligands towards both serotonin receptors.


Assuntos
Buspirona/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Sítios de Ligação , Buspirona/análogos & derivados , Humanos , Ligantes , Modelos Moleculares , Receptor 5-HT2A de Serotonina , Receptores de Serotonina/química , Receptores 5-HT1 de Serotonina , Relação Estrutura-Atividade
9.
Chirality ; 11(10): 790-4, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10561710

RESUMO

A series of 1,4-disubstituted piperazine derivatives with hypnotic activity were examined on three polysaccharide-based chiral stationary phases, namely, Chiracel OD, Chiracel OJ and Chiralpak AD. It was possible to resolve all the compounds on all the phases examined (1.13

10.
Solid State Nucl Magn Reson ; 14(1): 59-65, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10408275

RESUMO

13C cross-polarization (CP) magic angle spinning (MAS) solid state NMR spectra of hydrochlorides and perchlorates of buspirone analogues (2-5) were recorded. In the spectra for each compound, one set of signals appeared, in agreement with single crystal X-ray diffraction data indicating the presence of one molecule per crystal unit. The resonances of 2-5 hydrochlorides were assigned by comparison with the solution chemical shifts. For perchlorate 2b and diperchlorate 2c, the reasonable assignment of signals was made with the aid of the theoretical studies. Ab initio calculations of the carbon shieldings were performed by means of the GIAO-CHF method for two model systems: perchlorate and diperchlorate of quinoline-(N-methyl)piperazine. As no remarkable differences between carbon chemical shifts of hydrochlorides 3-5 in solid state and in solution were observed, it was concluded that in solution these compounds adopted the same conformation as in the solid state.


Assuntos
Buspirona/análogos & derivados , Buspirona/química , Imidas/química , Espectroscopia de Ressonância Magnética/métodos , Piperazinas/química , Isótopos de Carbono , Cloretos , Cristalografia por Raios X , Estrutura Molecular , Percloratos , Quinolinas/química , Serotonina
11.
J Chromatogr B Biomed Sci Appl ; 720(1-2): 65-9, 1998 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-9892068

RESUMO

The conditions of the chiral resolution of the racemic malathion O,O-di-n-alkyl derivatives on cellulose tris(3,5-dimethylphenylcarbamate) are described. Quantitative relationships between chromatographic parameters obtained on chiral and achiral stationary phases and acute toxicity of the compounds towards house fly are derived and discussed.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Inseticidas/química , Malation/química , Espectrofotometria Ultravioleta , Estereoisomerismo , Relação Estrutura-Atividade
12.
Solid State Nucl Magn Reson ; 13(1-2): 63-70, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9875604

RESUMO

13C CP (cross-polarization) MAS (magic angle spinning) solid state NMR spectra of buspirone analogue 3a,4,7,7a-tetrahydro-2-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-4,7-eth ane-1H-isoindole-1,3(2H)-dione were recorded. In the spectra of hydrochloride and hydrobromide, two sets of signals appeared, in agreement with single crystal X-ray diffraction data indicating that in each of the salts two independent cations were present in the crystal unit. The largest shielding differences of 3.2-4.6 ppm between two sets of signals were found for quinoline aromatic carbons C3 and C2. Ab initio calculations of the carbon and nitrogen shielding constants were performed with the use of the GIAO-CHF method for structural fragments: N-butylsuccinimide, quinoline-(N-methyl) piperazine hydrochloride and hydrobromide. Linear correlations between theoretical and solid state results were obtained, thus enabling a reasonable assignment of carbon resonances of the conformations present in the solid state. Due to the fast dynamics in solution, the carbon chemical shifts corresponded to the averaged values of the forms present in the solid state.


Assuntos
Ansiolíticos/química , Buspirona/análogos & derivados , Buspirona/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular
13.
J Pharm Pharmacol ; 49(7): 698-705, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9255714

RESUMO

A three-dimensional model of the 5-HT1A receptor in man was constructed by molecular-modelling techniques and used to study the molecular interactions of a series of buspirone analogues with the 5-HT1A receptor by molecular-mechanical-energy minimization and molecular-dynamics simulations. The receptor has seven trans-membrane alpha helices (TMHs) organized according to the electron-density-projection map of visual rhodopsin, and includes all loops between TMHs and the N- and C-terminal parts. The best fit between the buspirone analogues and the receptor model was obtained with the quinolinyl part of the ligand molecules interacting with amino acids in TMH6, the imide group interacting with amino acids in TMH2, TMH3 and TMH7, and the carbonyl groups hydrogen-bonded with Ser86 and Ser393. The ligand-binding rank order deduced from the experimentally determined inhibition constant was reproduced by calculation of receptor-binding energies of the buspirone analogues. The models suggest that steric hindrance and repulsive forces between the receptor and the imide group of the buspirone analogues are the most important determinants of ligand-binding affinity for discriminating between these ligands.


Assuntos
Buspirona/metabolismo , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Ligação Competitiva , Buspirona/análogos & derivados , Buspirona/farmacologia , Sequências Hélice-Alça-Hélice , Humanos , Ligação de Hidrogênio , Imidas/química , Ligantes , Masculino , Modelos Moleculares , Receptores de Serotonina/efeitos dos fármacos , Receptores 5-HT1 de Serotonina , Rodopsina/química , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacologia , Relação Estrutura-Atividade
14.
Arch Pharm (Weinheim) ; 330(5): 146-60, 1997 May.
Artigo em Inglês | MEDLINE | ID: mdl-9237427

RESUMO

Preparation and affinity to 5-HT1A and 5-HT2A receptors of new buspirone analogues 7-17 are reported. The compounds possess high to low affinity to 5-HT1A and moderate to low to 5-HT2A receptors. The crystal structures have been determined for compounds 11, 12, 13, and 14. For low affinity ligand (15) of 5-HT1A receptor conformational analysis was performed and compared with similar analyses performed for know high (buspirone 1) and very high (WY-48,723 2) affinity ligands of the receptor. Structure-activity relationship is discussed for the affinity to 5-HT1A receptor. A three-point pharmacophore explaining interactions of buspirone-like molecules with the receptor binding site is proposed.


Assuntos
Buspirona/química , Receptores de Serotonina/química , Agonistas do Receptor de Serotonina/química , Animais , Sítios de Ligação , Buspirona/metabolismo , Cristalografia , Modelos Moleculares , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores de Serotonina/metabolismo , Receptores 5-HT1 de Serotonina , Agonistas do Receptor de Serotonina/metabolismo , Relação Estrutura-Atividade
16.
Pharmazie ; 51(12): 924-7, 1996 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8985981

RESUMO

The lipophilicity of a series of buspirone related agents was studied by means of reversed-phase HPLC using an octadecylsilane stationary phase a mixture of aqueous solution of sodium phosphate and methanol as a mobile phase. Comparison of the measured capacity factors with log P values has shown very good correlations with regression correlation coefficients in the range of 0.994-0.996.


Assuntos
Buspirona/análogos & derivados , Buspirona/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Buspirona/química , Calibragem , Fenômenos Químicos , Físico-Química , Concentração de Íons de Hidrogênio , Indicadores e Reagentes , Ligantes , Receptores de Serotonina/química , Antagonistas da Serotonina/química
17.
Pol J Pharmacol ; 48(4): 431-40, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-9112684

RESUMO

Preparation, biological properties and QSAR of new derivatives of 1-[4-(2-pyrimidinyl)-1-piperazinyl]-1, 3-butandione (11-13, and 15-18) and 3-[4-(2-pirimidinyl)-1-piperazinyl]-3-oxopropanoate (20-22) exhibiting hypnotic activity in mice are reported. The best therapeutic indices (TI = LD50/ED50) 4.7 and 9.4 for po and ip administration, respectively, were found for 1-[4-(2-pyrimidinyl)-1-piperazinyl]-2-n-pentyl-1,3-butandione (15). QSAR studies showed that the biological activity grows initially with an increase in lipophilicity to drop dramatically for log P > 2.5.


Assuntos
Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Anfetamina/farmacologia , Animais , Anticonvulsivantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Interações Medicamentosas , Feminino , Hexobarbital/farmacologia , Hipnóticos e Sedativos/toxicidade , Dose Letal Mediana , Camundongos , Atividade Motora/efeitos dos fármacos , Piperazinas/toxicidade , Pirimidinas/toxicidade , Sono/efeitos dos fármacos , Relação Estrutura-Atividade
19.
Pol J Pharmacol ; 47(5): 445-9, 1995.
Artigo em Inglês | MEDLINE | ID: mdl-8868138

RESUMO

The effect of 5-morpholinemethyl-3-(4-chlorobenzylideneamino)-2-oxazolidin one (AS-8), a potential antidepressant drug, was tested on 5-hydroxytryptamine (5-HT) metabolism in the brains of rat, mouse and chick. The ip administration of AS-8 (25-500 mg/kg) did not modify the cerebral 5-HT level, but significantly increased the level of 5-hydroxyindoleacetic acid (5-HIAA) the main 5-HT metabolite. In animals receiving pargyline (a MAO-A inhibitor which blocks 5-HT catabolism), AS-8 markedly enhanced 5-HT accumulation in the brains of rats and mice, but not chicks. It is concluded that AS-8 is capable of stimulating of 5-HT synthesis at least in the mammalian brain.


Assuntos
Antidepressivos/farmacologia , Química Encefálica/efeitos dos fármacos , Morfolinas/farmacologia , Oxazóis/farmacologia , Oxazolidinonas , Serotonina/metabolismo , Animais , Galinhas , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos , Inibidores da Monoaminoxidase/farmacologia , Pargilina/farmacologia , Ratos , Fatores de Tempo
20.
J Med Chem ; 38(10): 1701-10, 1995 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-7752194

RESUMO

An interdisciplinary (X-ray, 1H and 13C NMR, IR, and theoretical quantum mechanical) study on the potent 5-HT1A receptor ligand buspirone (1) and its two structural analogues, mesmar (4,4-dimethyl-1-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-2,6- piperidinedione) (2) and kaspar (8-[4-[4-(2-quinolinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane - 7,9-dione) (3), has been reported. The results have shown that buspirone-like molecules should appear in an extended rod-shape form, possessing several potential interaction sites with the receptor.


Assuntos
Buspirona/análogos & derivados , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Buspirona/química , Buspirona/metabolismo , Isótopos de Carbono , Cátions , Eletroquímica , Ligantes , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piperazinas/química , Prótons
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