RESUMEN
Tetramethylenedisulfotetramine (TETS) is a so-called "caged" convulsant that is responsible for thousands of accidental and malicious poisonings. Similar to the widely used GABA receptor type A (GABAA) antagonist picrotoxinin, TETS has been proposed to bind to the noncompetitive antagonist (NCA) site in the pore of the receptor channel. However, the TETS binding site has never been experimentally mapped, and we here set out to gain atomistic level insights into how TETS inhibits the human α 2 ß 3 γ 2 GABAA receptor. Using the Rosetta molecular modeling suite, we generated three homology models of the α 2 ß 3 γ 2 receptor in the open, desensitized, and closed/resting state. Three different ligand-docking algorithms (RosettaLigand, Glide, and Swissdock) identified two possible TETS binding sites in the channel pore. Using a combination of site-directed mutagenesis, electrophysiology, and modeling to probe both sites, we demonstrate that TETS binds at the T6' ring in the closed/resting-state model, in which it shows perfect space complementarity and forms hydrogen bonds or makes hydrophobic interactions with all five pore-lining threonine residues of the pentameric receptor. Mutating T6' in either the α 2 or ß 3 subunit reduces the IC50 of TETS by â¼700-fold in whole-cell patch-clamp experiments. TETS is thus interacting at the NCA site in the pore of the GABAA receptor at a location that is overlapping but not identical to the picrotoxinin binding site. SIGNIFICANCE STATEMENT: Our study identifies the binding site of the highly toxic convulsant tetramethylenedisulfotetramine (TETS), which is classified as a threat agent by the World Health Organization. Using a combination of homology protein modeling, ligand docking, site-directed mutagenesis, and electrophysiology, we show that TETS is binding in the pore of the α2ß3γ2 GABA receptor type A receptor at the so-called T6' ring, wherein five threonine residues line the permeation pathway of the pentameric receptor channel.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/metabolismo , Convulsivantes/metabolismo , Receptores de GABA-A/metabolismo , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Hidrocarburos Aromáticos con Puentes/química , Convulsivantes/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Receptores de GABA-A/químicaRESUMEN
This paper focuses on determining the structural similarity of two molecules, i.e., the similarity of the interconnection of all the elementary cycles in the corresponding molecular graphs. In this paper, we propose and analyze an algorithmic approach based on the resolution of the Maximum Common Edge Subgraph (MCES) problem with graphs representing the interaction of cycles molecules. Using the ChEBI database, we compare the effectiveness of this approach in terms of structural similarity and computation time with two calculations of similarity of molecular graphs, one based on the MCES, the other on the use of different fingerprints (Daylight, ECFP4, ECFP6, FCFP4, FCFP6) to measure Tanimoto coefficient. We also analyze the obtained structural similarity results for a selected subset of molecules.
Asunto(s)
Diseño de Fármacos , Preparaciones Farmacéuticas/química , Algoritmos , Antineoplásicos/química , Gráficos por Computador , Convulsivantes/química , Docetaxel/química , Dopamina/química , Estructura Molecular , Estricnina/químicaRESUMEN
Technologies for mapping the spatial and temporal patterns of neural activity have advanced our understanding of brain function in both health and disease. An important application of these technologies is the discovery of next-generation neurotherapeutics for neurological and psychiatric disorders. Here, we describe an in vivo drug screening strategy that combines high-throughput technology to generate large-scale brain activity maps (BAMs) with machine learning for predictive analysis. This platform enables evaluation of compounds' mechanisms of action and potential therapeutic uses based on information-rich BAMs derived from drug-treated zebrafish larvae. From a screen of clinically used drugs, we found intrinsically coherent drug clusters that are associated with known therapeutic categories. Using BAM-based clusters as a functional classifier, we identify anti-seizure-like drug leads from non-clinical compounds and validate their therapeutic effects in the pentylenetetrazole zebrafish seizure model. Collectively, this study provides a framework to advance the field of systems neuropharmacology.
Asunto(s)
Mapeo Encefálico/métodos , Encéfalo/efectos de los fármacos , Aprendizaje Automático , Neurofarmacología/métodos , Animales , Animales Modificados Genéticamente , Encéfalo/patología , Encéfalo/fisiopatología , Convulsivantes/química , Convulsivantes/farmacología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Larva/efectos de los fármacos , Larva/fisiología , Estructura Molecular , Pentilenotetrazol/química , Pentilenotetrazol/farmacología , Convulsiones/tratamiento farmacológico , Convulsiones/fisiopatología , Pez CebraRESUMEN
The 'neurotrophic sesquiterpenes' refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other 'cage convulsant' compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.
Asunto(s)
Convulsivantes/metabolismo , Convulsivantes/farmacología , Progresión de la Enfermedad , Enfermedades Neurodegenerativas/metabolismo , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacología , Animales , Convulsivantes/química , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Factores de Crecimiento Nervioso/química , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Agitación Psicomotora/metabolismo , Sesquiterpenos/químicaRESUMEN
Drug-induced seizure liabilities produce significant compound attrition during drug discovery. Currently available in vitro cytotoxicity assays cannot predict all toxicity mechanisms due to the failure of these assays to predict sublethal target-specific electrophysiological liabilities. Identification of seizurogenic and other electrophysiological effects at early stages of the drug development process is important to ensure that safe candidate compounds can be developed while chemical design is taking place, long before these liabilities are discovered in costly preclinical in vivo studies. The development of a high throughput and reliable in vitro assay to screen compounds for seizure liabilities would de-risk compounds significantly earlier in the drug discovery process and with greater dependability. Here we describe a method for screening compounds that utilizes rat cortical neurons plated onto multiwell microelectrode array plates to identify compounds that cause neurophysiological disruptions. Changes in 12 electrophysiological parameters (spike train descriptors) were measured after application of known seizurogenic compounds and the response pattern was mapped relative to negative controls, vehicle control and neurotoxic controls. Twenty chemicals with a variety of therapeutic indications and targets, including GABAA antagonists, glycine receptor antagonists, ion channel blockers, muscarinic agonist, δ-opioid receptor agonist, dopaminergic D2/adrenergic receptor blocker and nonsteroidal anti-inflammatory drugs, were tested to assess this system. Sixteen of the seventeen seizurogenic/neurotoxic compounds tested positive for seizure liability or neurotoxicity, moreover, different endpoint response patterns for firing rate, burst characteristics and synchrony that distinguished the chemicals into groups relating to target and seizurogenic response emerged from the data. The negative and vehicle control compounds had no effect on neural activity. In conclusion, the multiwell microelectrode array platform using cryopreserved rat cortical neurons is a highly effective high throughput method for reliably screening seizure liabilities within an early de-risking drug development paradigm.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Convulsivantes/toxicidad , Evaluación Preclínica de Medicamentos/instrumentación , Microelectrodos , Neuronas/efectos de los fármacos , Convulsiones/inducido químicamente , Animales , Células Cultivadas , Convulsivantes/química , Relación Dosis-Respuesta a Droga , Ensayos Analíticos de Alto Rendimiento , Modelos Biológicos , Neuronas/fisiología , Valor Predictivo de las Pruebas , RatasRESUMEN
Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.
Asunto(s)
Convulsivantes/química , Oxazolidinonas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Convulsivantes/metabolismo , Convulsivantes/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacología , Ratas , Receptor del Glutamato Metabotropico 5/agonistas , Receptor del Glutamato Metabotropico 5/química , Reconocimiento en Psicología/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Covering: 1860-2016A mechanistic link may exist between convulsant plant substances typified by picrotoxinin, and 'neurotrophic' sesquiterpenes like jiadifenolide. Picrotoxinin elicits convulsion by anion blockade of the Cys-loop family of neurotransmitter-gated ion channels. These same receptors mediate neuronal development and neurite outgrowth prior to synapse formation. Due to its structural homology with picrotoxin and anisatin, it is possible that jiadifenolide enhances NGF-stimulated neurite outgrowth by modulation of the Cys-loop family of receptors.
Asunto(s)
Convulsivantes/farmacología , Neuritas/efectos de los fármacos , Sesquiterpenos/farmacología , Convulsivantes/química , Lactonas/química , Lactonas/farmacología , Estructura Molecular , Picrotoxina/análogos & derivados , Picrotoxina/química , Picrotoxina/farmacología , Sesquiterpenos/química , Sesterterpenos , Compuestos de Espiro/química , Compuestos de Espiro/farmacologíaRESUMEN
KEY POINTS: Most barbiturates are anaesthetics but unexpectedly a few are convulsants whose mechanism of action is poorly understood. We synthesized and characterized a novel pair of chiral barbiturates that are capable of photolabelling their binding sites on GABAA receptors. In mice the S-enantiomer is a convulsant, but the R-enantiomer is an anticonvulsant. The convulsant S-enantiomer binds solely at an inhibitory site. It is both an open state inhibitor and a resting state inhibitor. Its action is pH independent, suggesting the pyrimidine ring plays little part in binding. The inhibitory site is not enantioselective because the R-enantiomer inhibits with equal affinity. In contrast, only the anticonvulsant R-enantiomer binds to the enhancing site on open channels, causing them to stay open longer. The enhancing site is enantioselective. The in vivo actions of the convulsant S-enantiomer are accounted for by its interactions with GABAA receptors. ABSTRACT: Most barbiturates are anaesthetics but a few unexpectedly are convulsants. We recently located the anaesthetic sites on GABAA receptors (GABAA Rs) by photolabelling with an anaesthetic barbiturate. To apply the same strategy to locate the convulsant sites requires the creation and mechanistic characterization of a suitable agent. We synthesized enantiomers of a novel, photoactivable barbiturate, 1-methyl-5-propyly-5-(m-trifluoromethyldiazirinyl) phenyl barbituric acid (mTFD-MPPB). In mice, S-mTFD-MPPB acted as a convulsant, whereas R-mTFD-MPPB acted as an anticonvulsant. Using patch clamp electrophysiology and fast solution exchange on recombinant human α1 ß3 γ2L GABAA Rs expressed in HEK cells, we found that S-mTFD-MPPB inhibited GABA-induced currents, whereas R-mTFD-MPPB enhanced them. S-mTFD-MPPB caused inhibition by binding to either of two inhibitory sites on open channels with bimolecular kinetics. It also inhibited closed, resting state receptors at similar concentrations, decreasing the channel opening rate and shifting the GABA concentration-response curve to the right. R-mTFD-MPPB, like most anaesthetics, enhanced receptor gating by rapidly binding to allosteric sites on open channels, initiating a rate-limiting conformation change to stabilized open channel states. These states had slower closing rates, thus shifting the GABA concentration-response curve to the left. Under conditions when most GABAA Rs were open, an inhibitory action of R-mTFD-MPPB was revealed that had a similar IC50 to that of S-mTFD-MPPB. Thus, the inhibitory sites are not enantioselective, and the convulsant action of S-mTFD-MPPB results from its negligible affinity for the enhancing, anaesthetic sites. Interactions with these two classes of barbiturate binding sites on GABAA Rs underlie the enantiomers' different pharmacological activities in mice.
Asunto(s)
Anticonvulsivantes/farmacología , Convulsivantes/farmacología , GABAérgicos/farmacología , Fenobarbital/análogos & derivados , Receptores de GABA-A/metabolismo , Potenciales de Acción , Regulación Alostérica , Animales , Anticonvulsivantes/química , Convulsivantes/química , GABAérgicos/química , Células HEK293 , Humanos , Activación del Canal Iónico , Isomerismo , Masculino , Ratones , Fenobarbital/química , Fenobarbital/farmacología , Receptores de GABA-A/química , XenopusRESUMEN
Together with NOE and Jâ coupling, one-bond residual dipolar coupling (RDC), which reports on the three-dimensional orientation of an internuclear vector in the molecular frame, plays an important role in the conformation and configuration analysis of small molecules in solution by NMR spectroscopy. When the molecule has few C-H bonds, or too many bonds are in parallel, the available RDCs may not be sufficient to obtain the alignment tensor used for structure elucidation. Long-range RDCs that connect nuclei over multiple bonds are normally not parallel to the single bonds and therefore complement one-bond RDCs. Herein we present a method for extracting the long-range RDC of a chosen proton or group of protons to all remotely connected carbon atoms, including non-protonated carbon atoms. Alignment tensors fitted directly to the total long-range couplings (T=J+D) enabled straightforward analysis of both the long-range and one-bond RDCs for strychnine.
Asunto(s)
Convulsivantes/química , Espectroscopía de Resonancia Magnética/métodos , Estricnina/química , Algoritmos , Conformación Molecular , ProtonesRESUMEN
The density functional theoretical (DFT) computations were performed at the B3LYP/6-311G++(d, p) level to calculate the equilibrium geometry, vibrational wave numbers, intensities, and various other molecular properties of brucine and strychnine, which were found in satisfactory agreement with the experimental data. The out-of-phase stretching modes of aromatic rings and carbonyl stretching modes in combination with CH stretching modes at stereogenic centers generate VCD signals, which are remarkably efficient configuration markers for these chiral molecular systems. NBOs analysis reveals that the large values of second order perturbation energy (47.24kcal/mol for brucine and 46.93kcal/mol for strychnine) confirms strong hyperconjugative interaction between the orbital containing the lone pair of electron of nitrogen and the neighboring CO antibonding orbital. The molecular electrostatic potential map of strychnine molecule, with no polar groups other than the lone keto group, shows less polarization, which accounts for its lower susceptibility towards electrophilic attack as compared to brucine.
Asunto(s)
Analgésicos/química , Convulsivantes/química , Estricnina/análogos & derivados , Strychnos/química , Modelos Moleculares , Teoría Cuántica , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Electricidad Estática , Estricnina/química , TermodinámicaRESUMEN
A series of ring-constrained phenylpropyloxyethylamines, partial opioid structure analogs and derivatives of a previously studied sigma (σ) receptor ligand, was synthesized and evaluated at σ and opioid receptors for receptor selectivity. The results of this study identified several compounds with nanomolar affinity at both σ receptor subtypes. Compounds 6 and 9 had the highest selectivity for both σ receptor subtypes, compared to µ opioid receptors. In addition, compounds 6 and 9 significantly reduced the convulsive effects of cocaine in mice, which would be consistent with antagonism of σ receptors.
Asunto(s)
Ciclohexanoles/química , Etilaminas/química , Fenetilaminas/química , Propilaminas/química , Receptores sigma/antagonistas & inhibidores , Animales , Cocaína/química , Cocaína/toxicidad , Convulsivantes/química , Convulsivantes/metabolismo , Convulsivantes/uso terapéutico , Ciclohexanoles/metabolismo , Ciclohexanoles/uso terapéutico , Etilaminas/metabolismo , Etilaminas/uso terapéutico , Ratones , Fenetilaminas/metabolismo , Fenetilaminas/uso terapéutico , Propilaminas/metabolismo , Propilaminas/uso terapéutico , Unión Proteica , Receptores sigma/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológicoRESUMEN
A user-friendly 2D NMR approach denoted as CLIP-HSQMBC is proposed for the very easy, direct and accurate measurement of long-range proton-carbon coupling constants in organic molecules and natural products. The J value can be extracted directly from the analysis of resolved in-phase (1)H multiplets that show an additional splitting arising from the proton-carbon coupling. In cases of unresolved peaks, a simple fitting analysis using the internal satellite lines as a reference is performed. Addition of a spin-lock period results in a CLIP-HSQMBC-TOCSY experiment that is suitable for the measurement of very small coupling values or to observe correlations from overlapped resonances.
Asunto(s)
Carbono/química , Espectroscopía de Resonancia Magnética/métodos , Protones , Convulsivantes/química , Estricnina/químicaRESUMEN
Oenanthotoxin (OETX) and dihydro-OETX are polyacetylenic diols occurring in Oenanthe crocata and are known to exert proconvulsant effects. We have recently demonstrated that these compounds downregulated GABAergic currents (Appendino et al., 2009) and that OETX induced open channel block and allosterically modulated GABA(A) receptors (Wyrembek et al., 2010). O. crocata also contains several minor OETX analogues and in the present study we tested whether their effect on GABA(A) receptors depends on the compounds' polarity. We investigated a series of five polyacetylenes characterized by a higher lipophylicity than OETX, (1-acetyl-2,3-dihydrooenanthotoxin - X1, 14-acetyloenanthotoxin-X2, 1-deoxyoenanthotoxin - X3, 14-deoxyoenanthotoxin - X4, 14-dehydro-1-deoxyOETX - X5, polarity sequence: X1>X2>X3>X4>X5). Their effects were tested first on miniature inhibitory postsynaptic currents (mIPSCs). All but X3, significantly decreased the mIPSC amplitudes while X1, X2, X4 decreased, and X3 and X5 increased the mIPSC frequency. The lack of a clear correlation between the compounds' polarity and their effect on mIPSCs might result from their presynaptic effects. We thus considered their impact on current responses to exogenous GABA applications. Amplitude reduction of current responses was most prominent for X1 and virtually absent for X5 indicating a dependence on the compound's polarity. Only X1 and X2 showed open channel block, while the kinetics of currents were affected only by X1 which further supports a dependence of the drug's effects on their polarity. In conclusion, GABA(A) receptors are inhibited and allosterically modulated by naturally occurring OETX analogues (except X5) and these effects are positively correlated with the compounds' polarity.
Asunto(s)
Enediinos/química , Alcoholes Grasos/química , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Poliinos/farmacología , Transmisión Sináptica/efectos de los fármacos , Animales , Animales Recién Nacidos , Anticonvulsivantes/química , Anticonvulsivantes/aislamiento & purificación , Anticonvulsivantes/farmacología , Células Cultivadas , Convulsivantes/química , Convulsivantes/aislamiento & purificación , Convulsivantes/farmacología , Descubrimiento de Drogas , Enediinos/farmacología , Alcoholes Grasos/farmacología , Agonistas de Receptores de GABA-A/química , Agonistas de Receptores de GABA-A/aislamiento & purificación , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/aislamiento & purificación , Hipocampo/citología , Hipocampo/metabolismo , Interacciones Hidrofóbicas e Hidrofílicas , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Estructura Molecular , Neuronas/citología , Neuronas/metabolismo , Oenanthe/química , Raíces de Plantas/química , Poliinos/química , Poliinos/aislamiento & purificación , Ratas , Ratas WistarRESUMEN
A novel family of functionalized peptide toxins, aculeines (ACUs), was isolated from the marine sponge Axinyssa aculeate. ACUs are polypeptides with N-terminal residues that are modified by the addition of long-chain polyamines (LCPA). Aculeines were present in the sponge extract as a complex mixture with differing polyamine chain lengths and peptide structures. ACU-A and B, which were purified in this study, share a common polypeptide chain but differ in their N-terminal residue modifications. The amino acid sequence of the polypeptide portion of ACU-A and B was deduced from 3' and 5' RACE, and supported by Edman degradation and mass spectral analysis of peptide fragments. ACU induced convulsions upon intracerebroventricular (i.c.v.) injection in mice, and disrupted neuronal membrane integrity in electrophysiological assays. ACU also lysed erythrocytes with a potency that differed between animal species. Here we describe the isolation, amino acid sequence, and biological activity of this new group of cytotoxic sponge peptides.
Asunto(s)
Péptidos/química , Péptidos/aislamiento & purificación , Poliaminas/química , Poliaminas/metabolismo , Poríferos/química , Toxinas Biológicas/química , Toxinas Biológicas/aislamiento & purificación , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Clonación Molecular , Convulsivantes/química , Convulsivantes/aislamiento & purificación , Convulsivantes/metabolismo , Convulsivantes/toxicidad , Células HEK293 , Hemólisis/efectos de los fármacos , Humanos , Ratones , Datos de Secuencia Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Mapeo Peptídico , Péptidos/metabolismo , Péptidos/toxicidad , Poríferos/genética , Análisis de Secuencia de ADN , Toxinas Biológicas/metabolismo , Toxinas Biológicas/toxicidadRESUMEN
The development of robust and predictive QSAR models is highly dependent on the use of molecular descriptors that contain information relevant to the property being modelled. Selection of these relevant features from a large pool of possibilities is difficult to achieve effectively. Modern Bayesian methods provide substantial advantages over conventional feature selection methods for feature selection and QSAR modelling. We illustrate the importance of descriptor choice and the beneficial properties of Bayesian methods to select context-dependent relevant descriptors and build robust QSAR models, using data on anaesthetics. Our results show the effectiveness of Bayesian feature selection methods in choosing the best descriptors when these are mixed with less informative descriptors. They also demonstrate the efficacy of the Abraham descriptors and identify deficiencies in ParaSurf descriptors for modelling anaesthetic action.
Asunto(s)
Anestésicos/química , Convulsivantes/química , Relación Estructura-Actividad Cuantitativa , Anestésicos/farmacología , Anestésicos por Inhalación , Teorema de Bayes , Convulsivantes/farmacología , Modelos LinealesRESUMEN
The convulsant activity of 48 compounds studied by Eger et al. has been analyzed using an Abraham solvation equation. Four compounds identified by Eger et al. as more potent than expected were similarly identified, and for the remaining 44 compounds, the equation had R(2)=0.978 and a standard deviation of 0.17 log units. The structural features of compounds that lead to convulsant activity or to anesthetic activity are uncovered, and used to explain which compounds will act as convulsants and which compounds will act as anesthetics. The present equation for convulsant activity and our previous equation for inhalation anesthetic activity can be used to predict convulsant pressure and anesthetic pressure. For all 48 compounds, the predicted convulsant pressure is less than the predicted anesthetic pressure, in agreement with experiment. Although convulsants tend to have a small hydrogen bond acidity, this is not the only factor that influences the effect. The difference between the compound pressure needed to produce convulsions and that needed to produce anesthesia is quite small for many of the 48 compounds, and so minor structural features can be significant. These structural features are incorporated into our equations that successfully predict convulsant/anesthetic effects for the 48 compounds.
Asunto(s)
Convulsivantes/farmacología , Gases , Relación Estructura-Actividad Cuantitativa , Anestésicos/química , Anestésicos/farmacología , Animales , Convulsivantes/química , Enlace de Hidrógeno , Presión , Ratas , VolatilizaciónRESUMEN
Recently we identified (R,S)-2-acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6) as a potent non-competitive AMPA receptor antagonist able to prevent epileptic seizures. We report here the optimized synthesis of compound 6, its resolution by chiral preparative HPLC, and the absolute configuration of (R)-enantiomer established by X-ray diffractometry. The biological tests of the single enantiomers revealed that higher anticonvulsant and antagonistic effects reside in (R)-enantiomer as also suggested by molecular modeling studies.
Asunto(s)
Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Modelos Moleculares , Receptores de Glutamato/metabolismo , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/uso terapéutico , Animales , Convulsivantes/síntesis química , Convulsivantes/química , Convulsivantes/uso terapéutico , Cristalografía por Rayos X , Antagonistas de Aminoácidos Excitadores/química , Masculino , Ratones , Estructura Molecular , Ratas , Convulsiones/tratamiento farmacológico , Convulsiones/patología , Estereoisomerismo , Tetrahidroisoquinolinas/químicaRESUMEN
It has been reported that 2-(4-substituted thiazol-2-ylthio)-1beta-methyl-carbapenems exhibit potent activity against methicillin-resistant staphylococci (MRS) and vancomycin-resistant enterococci (VRE). In order to develop a novel broad-spectrum carbapenem, the structure-activity relationships of a series of 2-(4-tetrahydropyridinylthiazol-2-ylthio)-1beta-methylcarbapenems and 4-dihydropyrrolyl thiazole analogs were investigated with regard to their activity against Gram-positive and especially Gram-negative bacteria and also their convulsant activity, which is a major side effect concern of carbapenems. The introduction of substituent(s) on the dihydropyrrole moiety did not cause remarkable changes in anti-MRS and VRE activities, but tended to lower the anti-Gram-negative bacterial activity except in some cases of methyl group introduction. These substitutions did however cause a reduction of the convulsant activity, which was affected by the size and also the configuration of the substituent. In the case of SM-216601 (6), introduction of a methyl group brought about significant reduction in neurotoxicity while maintaining favorable anti-Gram-negative bacterial activity.
Asunto(s)
Bacterias/efectos de los fármacos , Carbapenémicos/farmacología , Convulsivantes/farmacología , Animales , Carbapenémicos/química , Carbapenémicos/toxicidad , Convulsivantes/química , Convulsivantes/toxicidad , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos ICR , Pruebas de Sensibilidad Microbiana , Convulsiones/inducido químicamente , Espectrofotometría Infrarroja , Espectroscopía Infrarroja por Transformada de Fourier , Relación Estructura-ActividadRESUMEN
Two glutamic acid analogs, (+)-(S)- and (-)-(R)-4-(2,2-diphenyl-1,3,2-oxazaborolidin-5-oxo)propionic acid ((+)-(S)- and (-)-(R)-Trujillon, respectively), were prepared. The stereospecific activity of their pharmacological properties was studied. The median convulsant dose (CD(50)) and median lethal dose (LD(50)) were analyzed in female Swiss Webster mice and their effects in vivo on unitary electrical activity in globus pallidus neurons were elucidated in male Wistar rats. Compounds were characterized by (1)H, (13)C, and (11)B nuclear magnetic resonance. The LD(50) of (+)-(S)-Trujillon was 449.08 mg/kg and it increased spontaneous motor activity, while with (-)-(R)-Trujillon there was no mortality up to 1,000 mg/kg and it decreased spontaneous motor activity. The CD(50) in experiments with (+)-(S)-Trujillon was 199.34 mg/kg. Unitary recording in globus pallidus neurons showed i.v. administration (+)-(S)-Trujillon (50 mg/kg) increased frequency 79.0 +/- 23.0% in relation to basal response. (-)-(R)-Trujillon and (+)-(S)-glutamate (50 mg/kg each) did not provoke changes in spontaneous basal firing. Local infusion of (+)-(S)-Trujillon (1 nMol) increased spontaneous firing in most neurons tested by 269.0 +/- 83.0% in relation to basal values. Intrapallidal infusion of (-)-(R)-Trujillon (1 nMol) and saline solution did not cause statistically significant changes in globus pallidus spiking. Results showed that (+)-(S)-Trujillon crosses the blood-brain barrier and has stereospecific activity.
Asunto(s)
Compuestos de Boro/síntesis química , Glutamatos/química , Ácido Glutámico/análogos & derivados , Ácido Glutámico/síntesis química , Animales , Compuestos de Boro/farmacología , Compuestos de Boro/toxicidad , Convulsivantes/síntesis química , Convulsivantes/química , Convulsivantes/farmacología , Difusión , Relación Dosis-Respuesta a Droga , Potenciales Evocados/efectos de los fármacos , Femenino , Globo Pálido/citología , Globo Pálido/efectos de los fármacos , Glutamatos/farmacología , Glutamatos/toxicidad , Ácido Glutámico/farmacología , Ácido Glutámico/toxicidad , Indicadores y Reactivos , Inyecciones Intravenosas , Dosificación Letal Mediana , Ratones , Neuronas/efectos de los fármacos , Estereoisomerismo , Telencéfalo/citología , Telencéfalo/efectos de los fármacosRESUMEN
Nonselective inverse agonists at the gamma-aminobutyric acid(A) (GABA-A) benzodiazepine binding site have cognition-enhancing effects in animals but are anxiogenic and can precipitate convulsions. Herein, we describe novel GABA-A alpha5 subtype inverse agonists leading to the identification of 16 as an orally active, functionally selective compound that enhances cognition in animals without anxiogenic or convulsant effects. Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias.