RESUMEN

Glutamate is the major excitatory neurotransmitter and known to activate the metabotropic and ionotropic glutamate receptors in the brain. Among these glutamate receptors, metabotropic glutamate receptor 1 (mGluR1) has been implicated in various brain disorders including anxiety, schizophrenia and chronic pain. Several studies demonstrated that the blockade of mGluR1 signaling reduced pain responses in animal models, suggesting that mGluR1 is a promising target for the treatment of neuropathic pain. In this study, we have developed mGluR1 antagonists with an aryl isoxazole scaffold, and identify several compounds that are orally active in vivo. We believe that these compounds can serve as a useful tool for the investigation of the role of mGluR1 and a promising lead for the potential treatment of neuropathic pain.

Asunto(s)

Analgésicos/síntesis química , Isoxazoles/química , Neuralgia/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Isoxazoles/uso terapéutico , Neuralgia/inducido químicamente , Unión Proteica , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad

RESUMEN

The T-type Ca(2+) channel is a low-voltage-activated Ca(2+) channel related to nociceptive stimuli. Increases in Ca(2+) due to calcium channel activation enhance pain sensitivity through both peripheral and central pain pathways. We have developed a novel compound, KST5468, which is a T-type calcium channel antagonist. The new synthetic compound may have an antinociceptive effect, and thus we evaluated KST5468 as a putative analgesic in a hot plate test, a formalin test, and two neuropathic pain models. KST5468 caused a significant increase in latency in the hot plate test at 30min after a 10mg/kg peritoneal injection of the compound. Interestingly, in the second phase of formalin test, KST5468 decreased pain behaviors in a dose-dependent manner. Moreover, in two neuropathic pain models induced by chronic constriction and spared nerve injury, KST5468 significantly increased the mechanical pain threshold. Using immunohistochemistry, expression of two well known pain-related molecular markers, c-Fos and calcitonin gene-related peptide (CGRP), and phosphorylated extracellular signal-related kinase (p-ERK) were found to be decreased in the laminae I-II layers of the ipsilateral L4-L5 spinal dorsal horn in KST5468 treated mice. Taken together, the results of this study suggest that KST5468 may be an effective antinociceptive agent for neuropathic pain.

Asunto(s)

Analgésicos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Inflamación/complicaciones , Isoxazoles/metabolismo , Neuralgia/tratamiento farmacológico , Dimensión del Dolor/efectos de los fármacos , Piperazinas/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/biosíntesis , Bloqueadores de los Canales de Calcio/farmacocinética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Formaldehído , Expresión Génica/efectos de los fármacos , Genes fos/efectos de los fármacos , Calor , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Isoxazoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos ICR , Neuralgia/etiología , Piperazinas/farmacocinética , Equilibrio Postural/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos

RESUMEN

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives substituted with arylpiperazinylalkylamines. The oxazoles were synthesized in a convenient convergent synthetic method, and biologically evaluated against alpha(1G) (Ca(V)3.1) T-type calcium channel. Among total 41 oxazole compounds synthesized, the most active one was the compound 10-35 with an IC(50) value of 0.65 microM, which is comparable with that of mibefradil.

Asunto(s)

Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Oxazoles/farmacología , Evaluación Preclínica de Medicamentos

RESUMEN

We have investigated halogen-substituted non-steroidal estrogens with selective binding affinity for the estrogen receptor beta (ERbeta that might be used for imaging the levels of this ER-subtype in breast tumors by positron emission tomography (PET). Based on diarylpropionitrile (DPN, 1a), a compound previously reported that has a 72-fold binding selectivity for ERbeta, we developed a series of DPN analogs having methyl-, hydroxyl-, and halogen substituents, including fluoroethyl and fluoropropyl groups. In competitive radiometric binding assays with [(3)H]estradiol, all of these DPN analogs showed high ERbeta/ERalpha selectivity; while the selectivity varied, in some cases it reached nearly 300-fold (RBA: ERalpha, 0.023%; ERbeta, 6.25%). The absolute ERbeta binding affinities, however, were not sufficient to merit further consideration for developing these ligands as PET imaging agents.

Asunto(s)

Receptor beta de Estrógeno/metabolismo , Nitrilos/síntesis química , Propionatos/síntesis química , Radiofármacos/síntesis química , Unión Competitiva , Receptor beta de Estrógeno/química , Radioisótopos de Flúor/química , Humanos , Cinética , Ligandos , Nitrilos/química , Tomografía de Emisión de Positrones , Propionatos/química , Unión Proteica , Radiofármacos/química , Relación Estructura-Actividad , Especificidad por Sustrato

RESUMEN

5-HT(7) receptor antagonists generated antidepressant-like effects in animal model and the involvement of the 5-HT(7) receptor in other pathophysiological mechanisms such as thermoregulation, learning and memory, and sleep has been highlighted by various studies. As one of our efforts to discover a new type of 5-HT(7) receptor antagonists, we here report on the synthesis and binding affinities to the 5-HT(7) receptor of the quinazolinone library 1, which was designed with various substituents (X, Y, R(1), and R(2)) on the aromatic rings and different carbon chain length. Total 85 compounds of the quinazolinone library 1 were synthesized and the binding affinities of all the synthesized compounds were obtained by radioligand binding assay for the 5-HT(7) receptor. Among the 85 compounds, 24 compounds show very good binding affinities with IC(50) values below 100 nM. Mainly the compounds with IC(50) values below 100 nM have o-OMe or o-OEt as R(2) substituent. The compound with the best binding affinity is 1-68 of which the IC(50) value is 12 nM. In in vivo animal study, some synthesized compounds really have the antidepressant activity in the forced swimming test in mice.

Asunto(s)

Quinazolinonas/síntesis química , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Animales , Antidepresivos/síntesis química , Antidepresivos/química , Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Ligandos , Ratones , Estructura Molecular , Neurotransmisores/síntesis química , Neurotransmisores/química , Quinazolinonas/química , Quinazolinonas/uso terapéutico , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Relación Estructura-Actividad , Natación

RESUMEN

Comparative quantitative structure-activity relationship (QSAR) analyses of peptide deformylase (PDF) inhibitors were performed with a series of previously published (British Biotech Pharmaceuticals, Oxford, UK) reverse hydroxamate derivatives having antibacterial activity against Escherichia coli PDF, using 2D and 3D QSAR methods, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR). Statistically reliable models with good predictive power were generated from all three methods (CoMFA r (2) = 0.957, q (2) = 0.569; CoMSIA r (2) = 0.924, q (2) = 0.520; HQSAR r (2) = 0.860, q (2) = 0.578). The predictive capability of these models was validated by a set of compounds that were not included in the training set. The models based on CoMFA and CoMSIA gave satisfactory predictive r (2) values of 0.687 and 0.505, respectively. The model derived from the HQSAR method showed a low predictability of 0.178 for the test set. In this study, 3D prediction models showed better predictive power than 2D models for the test set. This might be because 3D information is more important in the case of datasets containing compounds with similar skeletons. Superimposition of CoMFA contour maps in the active site of the PDF crystal structure showed a meaningful correlation between receptor-ligand binding and biological activity. The final QSAR models, along with information gathered from 3D contour and 2D contribution maps, could be useful for the design of novel active inhibitors of PDF.

Asunto(s)

Amidohidrolasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Proteínas de Escherichia coli/antagonistas & inhibidores , Escherichia coli/enzimología , Relación Estructura-Actividad Cuantitativa , Antibacterianos/síntesis química , Antibacterianos/farmacología , Diseño de Fármacos , Farmacorresistencia Bacteriana , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Proteínas de Escherichia coli/biosíntesis , Modelos Químicos

RESUMEN

The asymmetric synthesis of chiral piperazinylpropylisoxazoline analogues, (R)-(+)-1, 2 and (S)-(-)-1, 2 was accomplished through a seven-step sequence of reactions, which involved asymmetric 1,3-dipolar cycloaddition, alkyl chain extension, and reductive amination as key reactions. Chiral ligands (R)-(+)-1, 2 exhibited the higher binding affinity and selectivity for the D(3) receptor over the D(4) receptor than (S)-(-)-1, 2 ligands.

Asunto(s)

Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Isoxazoles/síntesis química , Isoxazoles/farmacología , Receptores Dopaminérgicos/metabolismo , Antagonistas de Dopamina/metabolismo , Isoxazoles/metabolismo , Modelos Moleculares , Unión Proteica , Receptores Dopaminérgicos/química , Relación Estructura-Actividad

RESUMEN

Virtual screening of the commercial databases was done by using a three dimensional pharmacophore previously developed for T-type calcium channel blockers using CATALYSTtrade mark program. Biological evaluation of 25 selected virtual hits resulted in the discovery of a highly potent compound VH04 with IC(50) value of 0.10 microM, eight times as potent as the known selective T-type calcium channel blocker, mibefradil. Search for similar compounds yielded several hits with micro-molar IC(50) values and high T-type calcium channel selectivity. Based on the structure of the virtual hits, small molecule libraries with novel scaffolds were designed, synthesis and biological evaluation of which are currently in progress. This result shows a successful example of ligand based drug discovery of potent T-type calcium channel blockers.

Asunto(s)

Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Animales , Canales de Calcio Tipo N/efectos de los fármacos , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo T/genética , Catálisis , Línea Celular , Simulación por Computador , Bases de Datos Factuales , Electrofisiología , Humanos , Mibefradil/farmacología , Modelos Moleculares , Oocitos/metabolismo , Técnicas de Placa-Clamp , ARN Complementario/biosíntesis , ARN Complementario/genética , Xenopus

RESUMEN

T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pains. Since the withdrawal of mibefradil, a T-type calcium channel blocker, there have been a lot of efforts to develop T-type calcium channel blockers. A small molecule library of dioxoquinazoline carboxamide derivatives containing 155 compounds was designed, synthesized, and biologically evaluated for T-type calcium channel blocking activity. Among those compounds synthesized, the compound 1n shows the most potent T-type calcium current blocking activity with an IC(50) value of 1.52 microM, which is comparable to that of mibefradil.

Asunto(s)

Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Quinazolinas/farmacología , Amidas/síntesis química , Amidas/química , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/química , Línea Celular , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Quinazolinas/síntesis química , Quinazolinas/química , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

A data set of 130 diverse compounds containing both central nervous system (CNS) and non-CNS drugs was used to generate a renal clearance model using a classical Volsurf approach. Percentage renal clearance data was used as a biological input. The score plots obtained from principal component analysis and partial least-squares (PLS) analysis clearly separated high-clearance compounds from low-clearance compounds. PLS models were used to predict the renal clearance of the data set. Categorical statistical methods such as SIMCA and recursive partitioning techniques were used for classifying the compounds into low- and high-clearance categories. PLS coefficient plots, Volsurf descriptor profiles, 3D Grid maps, and RP decision trees were used to explain the important descriptors separating low and high renal clearance compounds. For comparative purposes, topological descriptors such as Molconn-Z were also examined. All the models were validated by an external test set of 20 compounds. These models can be used as efficient tools in the classification and prediction of the renal clearance of unknown compounds, the knowledge of which is helpful in understanding their bioavailability behavior.

Asunto(s)

Riñón/fisiología , Modelos Biológicos , Humanos , Análisis de los Mínimos Cuadrados

RESUMEN

Dopamine antagonists (DA), serotonin antagonists (SA), and serotonin-dopamine dual antagonists (Dual) are being used as antipsychotics. A lot of dopamine and serotonin antagonists reveal non-selective binding affinity against these two receptors because the antagonists share structurally common features originated from conserved residues of binding site of the aminergic receptor family. Therefore, classification of dopamine and serotonin antagonists into their own receptors can be useful in the designing of selective antagonist for individual therapy of antipsychotic disorders. Data set containing 1135 dopamine antagonists (D2, D3, and D4), 1251 serotonin antagonists (5-HT1A, 5-HT2A, and 5-HT2C), and 386 serotonin-dopamine dual antagonists was collected from the MDDR database. Cerius2 descriptors were employed to develop a classification model for the 2772 compounds with antipsychotic activity. LDA (linear discriminant analysis), SIMCA (soft independent modeling of class analogy), RP (recursive partitioning), and ANN (artificial neural network) algorithms successfully classified the active class of each compound at the average 73.6% and predicted at the average 69.8%. The decision trees from RP, the best model, were generated to identify and interpret those descriptors that discriminate the active classes more easily. These classification models could be used as a virtual screening tool to predict the active class of new candidates.

Asunto(s)

Árboles de Decisión , Antagonistas de Dopamina/clasificación , Antagonistas de la Serotonina/clasificación , Algoritmos

RESUMEN

The designing of selective dopamine antagonists for their own subreceptors can be useful in individual therapy of various neuropsychiatric disorders. Three-dimensional pharmacophore hypothesis and two-dimensional topological descriptors were used to investigate and compare different classes of dopamine antagonists. The structurally diverse D(3) and D(4) antagonists above preclinical trials were selected to map common structural features of highly selective and efficacious antagonists. The generated pharmacophore hypotheses were successfully employed as discriminative probe for database screening. To filter out the false positive from screening hits, the classification models by two-dimensional topological descriptors were built. Molconn-Z and BCUT topological descriptors were employed to develop a classification model for 1328 dopamine antagonists from MDDR database. The soft independent modeling of class analogy and artificial neural network, two supervised classification techniques, successfully classified D(1), D(3), and D(4) antagonists at the average of 80% rates into their own active classes. The mean classification rates for D(2) antagonists were obtained to 60% due to insufficient selective D(2) antagonists. In this paper, we report the validity of our models generated using functional feature hypotheses and topological descriptors. The combining both of classification using functional feature hypotheses and topological descriptors would be a useful tool to predict selective antagonists.

Asunto(s)

Bases de Datos Factuales , Antagonistas de Dopamina/clasificación , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Receptores Dopaminérgicos/metabolismo , Algoritmos , Unión Competitiva , Antagonistas de Dopamina/química , Modelos Moleculares , Redes Neurales de la Computación , Relación Estructura-Actividad Cuantitativa

RESUMEN

KKHA-761, 1-{4-[3-(3,4-dimethoxy-phenyl)-isoxazol-5-yl]-butyl}-4-(2-methoxy-phenyl)-piperazine, has a high affinity (Ki=3.85 nM) for human dopamine D3 receptor with about 70-fold selectivity over the human dopamine D(2L) receptor (Ki=270 nM). KKHA-761 also showed high affinity for cloned human 5-HT1A receptor (Ki=6.4 nM). KKHA-761 exhibited D3 and 5-HT1A receptor antagonist activities in vitro, reversing dopamine- or 5-HT-mediated stimulation of [35S]GTPrS binding. The in vivo pharmacological profile of KKHA-761 was compared with both typical and atypical antipsychotics including clozapine and haloperidol. Apomorphine-induced dopaminergic behavior, cage climbing, in mice was potently blocked by a single administration (i.p.) of KKHA-761 (ID50=4.06 mg/kg) or clozapine (ID50=4.0 mg/kg). Cocaine- or MK-801-induced hyperactivity in animals was markedly inhibited by KKHA-761 or clozapine. In addition, KKHA-761 significantly reversed the disruption of prepulse inhibition (PPI) produced by apomorphine in mice, indicating the antidopaminergic or antipsychotic activity of KKHA-761 in mice. However, KKHA-761 was inactive in the forced swimming behavioral despair model in mice, suggesting lack of antidepressant properties. KKHA-761 attenuated the hypothermia induced by a selective dopamine D3 agonist, 7-OH-DPAT, in mice, whereas clozapine enhanced it. Moderate doses of both KKHA-761 and clozapine did not increase serum prolactin levels in rats. Lower doses of, however, haloperidol significantly increased prolactin secretion. KKHA-761 did not induce cataleptic response up to 20 mg/kg, but significant catalepsy was shown at lower doses of clozapine and haloperidol. Furthermore, KKHA-761 showed a low incidence of rotarod ataxia (TD50=34.4 mg/kg, i.p.) in mice. The present results, therefore, suggest that KKHA-761 is a potent antipsychotic agent with combined dopamine D3 and serotonin 5-HT1A receptors modulation activity, which may further enhance its therapeutic potential for anxiety, psychotic depression, and other related disorders.

Asunto(s)

Antipsicóticos , Isoxazoles/farmacología , Piperazinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Dopamina D3/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Animales , Temperatura Corporal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/psicología , Línea Celular , Inhibidores de Captación de Dopamina/farmacología , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Canales Iónicos/efectos de los fármacos , Canales Iónicos/metabolismo , Isoxazoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos ICR , Piperazinas/farmacocinética , Equilibrio Postural/efectos de los fármacos , Prolactina/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D4/efectos de los fármacos , Receptores de Dopamina D4/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Psicología del Esquizofrénico , Agonistas de Receptores de Serotonina/farmacología , Espiperona/metabolismo , Natación/psicología

RESUMEN

[reaction: see text]. A novel synthetic methodology for 2,5-disubstituted tetrahydrofurans having an allenyl group at the 3-position via Prins-type cyclization was developed. The reaction led to excellent selectivity and moderate to high yields.

RESUMEN

Classical Volsurf approach was applied to a set of 70 carbapenem compounds acting as antibiotics. Antibacterial activity of Staphylococcus aureus SG 511 and Escherichia coli 078 representing Gram positive and Gram negative bacteria, respectively, was used for the analysis. The score plots obtained from principal component analysis showed clustering of compounds according to the activity and their loading plots explained the Volsurf descriptors responsible for the separation or peculiar behaviour of these compounds. Partial Least Square analysis yielded a seven component model for S. aureus with a cross-validated r2 (q2) value of 0.684 and conventional r2 value of 0.883 and for E. coli it is a six component model with cross-validated r2 (q2) value of 0.514 and conventional r2 value of 0.756. Both the PCA and PLS models were validated by an external test set of 15 compounds. All the compounds of the test set were fairly predicted with residual values less than one log unit. Comparatively activity data of S. aureus (Gram positive) was better explained than E. coli (Gram negative) by these models.

Asunto(s)

Antibacterianos/química , Antibacterianos/farmacología , Carbapenémicos/química , Carbapenémicos/farmacología , Escherichia coli/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa

RESUMEN

A small molecule library of piperazinylalkylisoxazole derivatives containing about 600 compounds was designed, synthesized and evaluated for blocking effects on T-type Ca(2+) channel. Several ligands were identified to possess high inhibitory activity against the T-type Ca(2+) channel. The compound 21 with trifluoromethyl substituents at C(3)-position of phenyl group (R(1)) and C(2)-position of phenyl group (R(2)) showed the highest inhibitory activity with IC(50) value of 1.02 microM, which is comparable to that of mibefradil.

Asunto(s)

Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Isoxazoles/síntesis química , Isoxazoles/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Calcio/química , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/metabolismo , Línea Celular , Diseño de Fármacos , Humanos , Isoxazoles/química , Ligandos , Estructura Molecular , Piperazinas/química , Relación Estructura-Actividad

RESUMEN

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series of N(1)-arylsulfonylindole compounds as 5-HT(6) antagonists. Evaluation of 20 compounds served to establish the models. The lowest energy conformer of compound 1 obtained from random search was used as template for alignment. The best predictions were obtained with CoMFA standard model (q2 = 0.643, r2 = 0.939 ) and with CoMSIA combined steric, electrostatic, hydrophobic, and hydrogen bond acceptor fields (q2 = 0.584, r2 = 0.902 ). Both the models were validated by an external test set of eight compounds giving satisfactory predictive r2 values of 0.604 and 0.654, respectively. The information obtained from CoMFA and CoMSIA 3D contour maps can be used for further design of specific 5-HT(6) antagonists.

Asunto(s)

Indoles/química , Indoles/farmacología , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Estructura Molecular

RESUMEN

Predictive hologram quantitative structure activity relationship (HQSAR) models were developed for a series of arylsulfonamide compounds acting as specific 5-HT6 antagonists. A training set containing 48 compounds served to establish the model. The best HQSAR model was generated using atoms, bond, and connectivity as fragment distinction and 4-7 as fragment size showing cross-validated r2(q2) value of 0.702 and conventional r2 value of 0.971. The predictive ability of the model was validated by an external test set of 20 compounds giving satisfactory predictive r2 value of 0.678. The efficiency of HQSAR approach was further evidenced by the generation of predictive models for a training set containing 30 highly diverse, both specific and nonspecific 5-HT6 antagonists. The best HQSAR model for this training set was generated using atoms, bond, and connectivity as fragment distinction and 4-7 as fragment size showing cross-validated r2(q2) value of 0.693 and conventional r2 value of 0.923. This model was also validated by using an external test set of 10 compounds giving satisfactory predictive r2 value of 0.692. The contribution maps obtained from these models were used to explain the individual atomic contributions to the overall activity.

Asunto(s)

Receptores de Serotonina/efectos de los fármacos , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacología , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa

RESUMEN

A three-dimensional pharmacophore model was developed for T-type calcium channel blockers in order to map common structural features of highly active compounds by using CATALYST program. In the absence of three dimensional structure based information like binding mode and unavailability of more number of specific T-type calcium channel blockers, this hypothesis which consists of three hydrophobic regions, one hydrogen bond acceptor and one positive ionizable regions will act as a valuable tool in designing new ligands. Further more after the withdrawal of mibefradil, the first marketed T-type calcium channel blocker, due to the drug-drug interactions, there is an urgent need for more work in this interest.

Asunto(s)

Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/efectos de los fármacos , Diseño de Fármacos , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacología , División Celular/efectos de los fármacos , Línea Celular , Interacciones Farmacológicas , Humanos , Enlace de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Modelos Químicos , Modelos Moleculares , Estructura Molecular , Relación Estructura-Actividad

RESUMEN

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of isoxazolyl compounds as a potent T-type calcium channel blockers. A set of 24 structurally similar compounds served to establish the model. Four different conformations of the most active compound were used as template structures for the alignment, three of which were obtained from Catalyst pharmacophore modeling and one by using SYBYL random search option. All CoMFA and CoMSIA models gave cross-validated r(2) (q(2)) value of more than 0.5 and conventional r(2) value of more than 0.85. The predictive ability of the models was validated by an external test set of 10 compounds, which gave satisfactory pred r(2) values ranging from 0.577 to 0.866 for all models. Best predictions were obtained with CoMFA std model of Conformer no: 3 alignment (q(2)=0.756, r(2)=0.963), giving predictive r(2) value of 0.866 for the test set. CoMFA and CoMSIA contour maps were used to analyze the structural features of the ligands accounting for the activity in terms of positively contributing physicochemical properties: steric, electrostatic, hydrophobic and hydrogen bonding fields.

Asunto(s)

Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/química , Diseño de Fármacos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Modelos Químicos , Conformación Molecular , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados