RESUMEN
Halogenated analogues of the neurotoxic alkaloid muscimol were prepared with fluorine, iodine or trifluoromethyl at the 4 position of the isoxazole ring system. These compounds were investigated as agonists for GABAA receptors. Only the C-4 fluorine-containing analogue proved to be an active compound in these assays. The fluoro analogue was less active than muscimol, however it showed differential activity between synaptic (α1 ß2 γ2 ) and extrasynaptic (α4 ß2 γ) GABAA receptors, having a similar potency to the neurotransmitter GABA for the extrasynaptic (α4 ß2 γ) receptor.
Asunto(s)
Flúor/química , Agonistas del GABA/química , Muscimol/química , Animales , Cristalografía por Rayos X , Agonistas del GABA/síntesis química , Agonistas del GABA/metabolismo , Conformación Molecular , Muscimol/síntesis química , Muscimol/metabolismo , Oocitos/metabolismo , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Xenopus laevis/crecimiento & desarrollo , Xenopus laevis/metabolismoRESUMEN
Chemical manufacturing is conducted using either batch systems or continuous-flow systems. Flow systems have several advantages over batch systems, particularly in terms of productivity, heat and mixing efficiency, safety, and reproducibility. However, for over half a century, pharmaceutical manufacturing has used batch systems because the synthesis of complex molecules such as drugs has been difficult to achieve with continuous-flow systems. Here we describe the continuous-flow synthesis of drugs using only columns packed with heterogeneous catalysts. Commercially available starting materials were successively passed through four columns containing achiral and chiral heterogeneous catalysts to produce (R)-rolipram, an anti-inflammatory drug and one of the family of γ-aminobutyric acid (GABA) derivatives. In addition, simply by replacing a column packed with a chiral heterogeneous catalyst with another column packed with the opposing enantiomer, we obtained antipole (S)-rolipram. Similarly, we also synthesized (R)-phenibut, another drug belonging to the GABA family. These flow systems are simple and stable with no leaching of metal catalysts. Our results demonstrate that multistep (eight steps in this case) chemical transformations for drug synthesis can proceed smoothly under flow conditions using only heterogeneous catalysts, without the isolation of any intermediates and without the separation of any catalysts, co-products, by-products, and excess reagents. We anticipate that such syntheses will be useful in pharmaceutical manufacturing.
Asunto(s)
Técnicas de Química Sintética/instrumentación , Técnicas de Química Sintética/métodos , Rolipram/síntesis química , Antidepresivos , Catálisis , Agonistas del GABA/síntesis química , Agonistas del GABA/química , Estructura Molecular , Rolipram/química , Estereoisomerismo , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/químicaRESUMEN
BACKGROUND: R-etomidate possesses unique desirable properties but potently suppresses adrenocortical function. Consequently, efforts are being made to define structure-activity relationships with the goal of designing analogues with reduced adrenocortical toxicity. The authors explored the pharmacological impact of modifying etomidate's chiral center using R-etomidate, S-etomidate, and two achiral etomidate analogues (cyclopropyl etomidate and dihydrogen etomidate). METHODS: The γ-aminobutyric acid type A receptor modulatory potencies of drugs were assessed in oocyte-expressed α1(L264T)ß3γ2L and α1(L264T)ß1γ2L γ-aminobutyric acid type A receptors (for each drug, n = 6 oocytes per subtype). In rats, hypnotic potencies and durations of action were measured using a righting reflex assay (n = 26 to 30 doses per drug), and adrenocortical potencies were quantified by using an adrenocorticotropic hormone stimulation test (n = 20 experiments per drug). RESULTS: All four drugs activated both γ-aminobutyric acid type A receptor subtypes in vitro and produced hypnosis and suppressed adrenocortical function in rats. However, drug potencies in each model ranged by 1 to 2 orders of magnitude. R-etomidate had the highest γ-aminobutyric acid type A receptor modulatory, hypnotic, and adrenocortical inhibitory potencies. Respectively, R-etomidate, S-etomidate, and cyclopropyl etomidate were 27.4-, 18.9-, and 23.5-fold more potent activators of receptors containing ß3 subunits than ß1 subunits; however, dihydrogen etomidate's subunit selectivity was only 2.48-fold and similar to that of propofol (2.08-fold). S-etomidate was 1/23rd as potent an adrenocortical inhibitor as R-etomidate. CONCLUSION: The linkage between the structure of etomidate's chiral center and its pharmacology suggests that altering etomidate's chiral center may be used as part of a strategy to design analogues with more desirable adrenocortical activities and/or subunit selectivities.
Asunto(s)
Anestésicos Intravenosos/química , Anestésicos Intravenosos/farmacología , Carbono/química , Etomidato/análogos & derivados , Etomidato/farmacología , Corteza Suprarrenal/efectos de los fármacos , Enfermedades de la Corteza Suprarrenal/inducido químicamente , Enfermedades de la Corteza Suprarrenal/patología , Anestésicos Intravenosos/toxicidad , Animales , Etomidato/química , Femenino , Agonistas del GABA/síntesis química , Agonistas del GABA/química , Agonistas del GABA/farmacología , Hipnóticos y Sedantes/síntesis química , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Indicadores y Reactivos , Dosificación Letal Mediana , Masculino , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/efectos de los fármacos , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
Nitrogen-containing fused heterocycles comprise many compounds that demonstrate interesting biological activities. A new synthetic approach involving Mitsunobu alkylation of imidazoles, pyrroles, and indoles followed by palladium-catalyzed cyclization has been developed providing access to fused heterocycles with a defined stereochemistry α to nitrogen. While ethyl imidazole or indole carboxylates are good substrates for Mitsunobu alkylation with optically pure secondary benzylic alcohols, the corresponding pyrroles are poor substrates presumably due to the increased pK(a) of the NH. The presence of a synthetically versatile trichloroacetyl functional group on the pyrroles significantly reduces the pK(a) and thereby facilitates Mitsunobu alkylation. Subsequent cyclization of the alkylated products mediated by palladium in the presence or absence of a ligand gave fused heterocycles in good to excellent yields.
Asunto(s)
Química Farmacéutica/métodos , Agonistas del GABA/síntesis química , Hipnóticos y Sedantes/síntesis química , Imidazoles/síntesis química , Indoles/síntesis química , Pirroles/síntesis química , Alquilación , Ansiedad/tratamiento farmacológico , Catálisis , Ciclización , Etomidato/análisis , Etomidato/química , Etomidato/farmacología , Agonistas del GABA/análisis , Agonistas del GABA/farmacología , Humanos , Hipnóticos y Sedantes/análisis , Hipnóticos y Sedantes/farmacología , Imidazoles/análisis , Indoles/análisis , Espectroscopía de Resonancia Magnética , Estructura Molecular , Nitrógeno/química , Paladio/química , Pirroles/análisis , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Expansion of the D-ring of 19-norsteroids with incorporation of the steroid C-18 methyl group into a newly formed six-membered ring provides easy access to the chrysene ring system. By taking advantage of the symmetry of the chrysene ring system and avoiding meso chrysene intermediates, four optically pure 2,8-difunctionalized (C-2 hydroxyl group and C-8 oxo group) hexadecahydrochrysene diastereomers, and their corresponding optically pure enantiomers were prepared from 19-nortestosterone. The eight chrysene stereoisomers are of interest as starting materials for preparing chrysene analogues of physiologically important neurosteroids.
Asunto(s)
Química Farmacéutica/métodos , Crisenos/síntesis química , Agonistas del GABA/síntesis química , Antagonistas del GABA/síntesis química , Nandrolona/química , Neurotransmisores/síntesis química , Andrógenos/química , Cromatografía en Capa Delgada , Crisenos/análisis , Agonistas del GABA/análisis , Antagonistas del GABA/análisis , Humanos , Espectroscopía de Resonancia Magnética , Neurotransmisores/análisis , Pregnanos/química , Receptores de GABA/metabolismo , EstereoisomerismoRESUMEN
The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured.
Asunto(s)
Epilepsia/tratamiento farmacológico , Agonistas del GABA/farmacocinética , Profármacos/farmacocinética , Tiazinas/farmacocinética , Tionas/farmacocinética , Ácido gamma-Aminobutírico , Animales , Barrera Hematoencefálica/metabolismo , Epilepsia/inducido químicamente , Femenino , Agonistas del GABA/síntesis química , Masculino , Ratones , Modelos Animales , Pentilenotetrazol/toxicidad , Profármacos/síntesis química , Tiazinas/síntesis química , Tiazinas/química , Tionas/síntesis química , Tionas/químicaRESUMEN
In trials to preserve the pharmacological profile and improve the bioavailability via lipophilicity increment of baclofen 1 and searching for more potent and less toxic muscle relaxants and analgesics, nine substituted cyclic analogues of 1 were designed and synthesized. The target derivatives 5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one (11-19) were obtained through amide formation to the corresponding intermediates (2-10) followed by cyclization using acetic anhydride. The structures of the target compounds (11-19) were confirmed by IR, (1)H NMR, MS, and elemental analyses. The neuropharmacological activities of these lipophilic cyclic analogues (11-19) were assessed for their effects on motor activity, muscle relaxation, pain relief and impaired cognition, by intraperitoneal administration at a dose of 3mg/kg with reference to those of baclofen 1. Our results showed that compounds 11-14 are devoid of all of the tested pharmacological effects associated with 1. In all paradigms tested, undecyl, tridecyl, heptdec-8-enyl and benzyl substituted analogue derivatives (15, 16, 18, and 19) revealed a significant neurological activity being vividly favorable comparable with baclofen 1. 2-Benzyl-5-(4-chlorophenyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 19 is the most active candidate with high significant neurological potencies, while 5-(4-chlorophenyl)-2-(dec-8-enyl)-5,6-dihydro-1,3-oxazepin-7(4H)-one derivative 17 displayed activity at relatively higher time interval. These results probe a new structurally distinct class incorporating 1,3-oxazepine nucleus as promising candidates as GABA(B) agonists for further investigations.
Asunto(s)
Baclofeno/química , Trastornos del Conocimiento/tratamiento farmacológico , Diseño de Fármacos , Relajación Muscular/efectos de los fármacos , Oxazepinas/síntesis química , Oxazepinas/farmacología , Dolor/tratamiento farmacológico , Animales , Baclofeno/farmacología , Ciclización , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Agonistas del GABA/síntesis química , Agonistas del GABA/química , Agonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Interacciones Hidrofóbicas e Hidrofílicas , Inyecciones Intraperitoneales , Espectroscopía de Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/normas , Masculino , Ratones , Estructura Molecular , Actividad Motora/efectos de los fármacos , Oxazepinas/química , Receptores de GABA-B/química , Estándares de Referencia , EstereoisomerismoRESUMEN
We describe the synthesis of sugar-fused beta-disubstituted gamma-butyrolactones, gamma-butyrolactams and a lipophilic beta-disubstituted GABA analogue as potential GABA receptor ligands, where the pharmacophore is engineered into the carbohydrate scaffold in the form of a C-fructoside. The products were characterized for receptor binding studies of GABA(A) receptors.
Asunto(s)
4-Butirolactona/análogos & derivados , 4-Butirolactona/química , Fructosa/análogos & derivados , Fructosa/química , Agonistas del GABA/química , Lactamas/química , Animales , Unión Competitiva , Encéfalo/metabolismo , Agonistas del GABA/síntesis química , Antagonistas del GABA/síntesis química , Antagonistas del GABA/química , Lactamas/síntesis química , Ligandos , Muscimol/química , RatasRESUMEN
The preparation of chiral tetrahydropyridine-4-carboxylates as isoguvacine analogues and azasugars with a tertiary stereocenter from L-amino acids via diastereoselective a Baylis-Hillman reaction of N-allyl-Boc alpha-aminal, followed by ring-closing metathesis and dihydroxylation sequences, is reported.
Asunto(s)
Aminoácidos/química , Compuestos Aza/síntesis química , Técnicas Químicas Combinatorias , Agonistas del GABA/síntesis química , Piridinas/síntesis química , Compuestos Aza/química , Agonistas del GABA/química , Ácidos Isonicotínicos/síntesis química , Ácidos Isonicotínicos/química , Estructura Molecular , Piridinas/química , EstereoisomerismoRESUMEN
A series of ring-substituted analogues of imidazole-4-acetic acid (IAA, 4), a partial agonist at both GABAA and GABAC receptors (GABA = gamma-aminobutyric acid), have been synthesized. The synthesized compounds 8a-l have been evaluated as ligands for the alpha1beta2gamma2S GABAA receptors and the rho1 GABAC receptors using the FLIPR membrane potential (FMP) assay and by electrophysiology techniques. None of the tested compounds displayed activity at the GABAA receptors at concentrations up to 1000 microM. However, the 5-Me, 5-Ph, 5-p-Me-Ph, and 5-p-F-Ph IAA analogues, 8a,c,f,g, displayed full agonist activities at the rho1 receptors in the FMP assay (EC50 in the range 22-420 microM). Ligand-protein docking identified the Thr129 in the alpha1 subunit and the corresponding Ser168 residue in rho1 as determinants of the selectivity displayed by the 5-substituted IAA analogues. The fact that GABA, 4, and 8a displayed decreased agonist potencies at a rho1Ser168Thr mutant compared to the WT rho1 receptor strongly supported this hypothesis. However, in contrast to GABA and 4, which exhibited increased agonist potencies at a alpha1(Thr129Ser)beta2gamma2 mutant compared to WT GABAA receptor, the data obtained for 8a at the WT and mutant receptors were nonconclusive.
Asunto(s)
Agonistas del GABA/síntesis química , Imidazoles/síntesis química , Modelos Moleculares , Receptores de GABA/efectos de los fármacos , Animales , Encéfalo/metabolismo , Línea Celular , Agonistas del GABA/química , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Humanos , Imidazoles/química , Imidazoles/farmacología , Técnicas In Vitro , Ligandos , Potenciales de la Membrana/efectos de los fármacos , Mutación , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Estructura Terciaria de Proteína , Subunidades de Proteína/agonistas , Subunidades de Proteína/genética , Subunidades de Proteína/fisiología , Ensayo de Unión Radioligante , Ratas , Receptores de GABA/genética , Receptores de GABA/fisiología , Receptores de GABA-A/química , Receptores de GABA-A/fisiología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The development of a series of GABA(A) alpha2/alpha3 subtype selective pyridazine based benzodiazepine site agonists as anxiolytic agents with reduced sedative/ataxic potential is described, including the discovery of 16, a remarkably alpha3-selective compound ideal for in vivo study. These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability.
Asunto(s)
Ansiolíticos/farmacología , Ansiedad/tratamiento farmacológico , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Piridazinas/farmacología , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/síntesis química , Sitios de Unión , Agonistas del GABA/administración & dosificación , Agonistas del GABA/síntesis química , Humanos , Ligandos , Estructura Molecular , Piridazinas/administración & dosificación , Piridazinas/síntesis química , Ratas , Proteínas Recombinantes/agonistas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Agonistas del GABA/síntesis química , Agonistas de Receptores de GABA-A , Imidazoles/síntesis química , Piridinas/síntesis química , Animales , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Agonistas del GABA/química , Agonistas del GABA/farmacología , Humanos , Imidazoles/química , Imidazoles/farmacología , Ligandos , Ratones , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Proteínas Recombinantes/agonistas , Relación Estructura-ActividadRESUMEN
The present study describes the synthesis and pharmacological profiles of four novel pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine derivatives 2-5, which were structurally designed by using the sedative and analgesic drug zolpidem 1 as lead compound. The heterotricyclic system present in the target compounds 2-5 was constructed in good yields, exploiting a regioselective hetero Diels-Alder reaction of the key azabutadiene derivative 7 and functionalized N-phenylmaleimides 9-12. Additionally, we identified that 1-methyl-7-(4-nitrophenyl)-3-phenyl-3,6,7,8-tetrahydropyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8-dione derivative (LASSBio-873, 5) presented not only the most potent ability to promote sedation, which was similar to that induced by the standard benzodiazepine drug midazolam, but also potent central antinociceptive effect.
Asunto(s)
Analgésicos no Narcóticos/síntesis química , Analgésicos no Narcóticos/farmacología , Hipnóticos y Sedantes/síntesis química , Hipnóticos y Sedantes/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Analgésicos no Narcóticos/química , Animales , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Agonistas del GABA/síntesis química , Agonistas del GABA/química , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Hipnóticos y Sedantes/química , Ligandos , Masculino , Ratones , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Piridinas/química , Relación Estructura-Actividad Cuantitativa , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Sueño/efectos de los fármacos , ZolpidemRESUMEN
(3-tert-Butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine (1) was recently identified as a functionally selective, inverse agonist at the benzodiazepine site of GABA(A) alpha5 receptors and enhances performance in animal models of cognition. The routes of metabolism of this compound in vivo in rat have been well characterised, the identities of the major metabolites are confirmed by synthesis and their biological profiles were evaluated. An unusual oxidation of the pyrazolo[1,5-d][1,2,4]triazine core to the corresponding pyrazolo[1,5-d][1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed.
Asunto(s)
Agonistas del GABA/metabolismo , Agonistas del GABA/farmacocinética , Agonistas de Receptores de GABA-A , Isoxazoles/metabolismo , Isoxazoles/farmacocinética , Subunidades de Proteína/agonistas , Triazinas/metabolismo , Triazinas/farmacocinética , Animales , Perros , Relación Dosis-Respuesta a Droga , Agonistas del GABA/síntesis química , Hidrólisis , Isoxazoles/síntesis química , Macaca mulatta , Ratones , Conformación Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular , Triazinas/síntesis químicaRESUMEN
Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones are high affinity GABA(A) agonists. Compound 16d has good oral bioavailability in rat, functional selectivity for the GABA(A)alpha2 and alpha3-subtypes and is anxiolytic in a conditioned animal model of anxiety with minimal sedation observed at full BZ binding site occupancy.
Asunto(s)
Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Administración Oral , Animales , Ansiolíticos/síntesis química , Benzodiazepinas/metabolismo , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Agonistas del GABA/síntesis química , Humanos , Ratones , Estructura Molecular , Técnicas de Placa-Clamp , Ratas , Receptores de GABA-A , Proteínas Recombinantes/agonistas , Relación Estructura-ActividadRESUMEN
A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.
Asunto(s)
Agonistas del GABA/síntesis química , Hidrocarburos Aromáticos/química , Imidazoles/química , Paladio/química , Triazinas/síntesis química , Acetaldehído/análogos & derivados , Acetaldehído/química , Bromuros/química , Catálisis , Receptores de GABA-A , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
A practical synthesis of 2-[3-(4-fluoro-3-pyridin-3-yl-phenyl)-imidazo[1,2-a]pyrimidin-7-yl]-propan-2-ol (1), an oral GABA(A) alpha(2/3)-selective agonist, is described. The five-step process, which afforded 1 in 40% overall yield, included imidazopyrimidine 2 and pyridine boronic acid 4 as key fragments. The synthesis is highlighted by consecutive Pd-catalyzed coupling steps to assemble the final free base 1 in high yield and regioselectivity. A novel method for Pd removal in the final step is also described.
Asunto(s)
Agonistas del GABA/síntesis química , Paladio/química , Propanoles/síntesis química , Pirimidinas/síntesis química , Regulación Alostérica , Ácidos Borónicos/química , Catálisis , Imidazoles/química , Estructura Molecular , Oxidación-Reducción , Piridinas/química , Pirimidinas/química , EstereoisomerismoRESUMEN
Research aimed at developing selective drugs acting on gamma-aminobutyric acid (GABA)A receptors introduced compounds from diverse chemical classes unrelated to the 1,4-benzodiazepines, including flavonoids. These studies also revealed the potential use of inverse agonists as cognition-enhancing agents. Here we report pharmacological properties of the novel synthetic isoflavonoid 2-methoxy-3,8,9-trihydroxy coumestan (PCALC36). PCALC36 displaced [3H]flunitrazepam binding to rat brain synaptosomes with an IC50 of 13.8 microM. Scatchard analysis of the effect of PCALC36 showed a concentration-dependent reduction of the Bmax of [3H]flunitrazepam, without a marked change in Kd. This effect could be reversed by diluting and washing the preparation. Addition of 20-microM GABA shifted to the right the inhibition curve of PCALC36 on [3H]flunitrazepam binding (IC50 ratio of 0.68), which is characteristic for inverse agonists. PCALC36 produced little change in the GABAergic tonic currents recorded by whole-cell patch clamp in cultured rat hippocampal neurones, but it caused a 20% reduction in miniature inhibitory postsynaptic current amplitude and completely antagonised the full (direct) agonist midazolam in a quickly reversible manner. The data suggest that the coumestan backbone can be useful for developing novel ligands at the GABAA receptor.
Asunto(s)
Flavonoides/farmacología , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Isoflavonas/farmacología , Análisis de Varianza , Animales , Bicuculina/farmacología , Unión Competitiva/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Flavonoides/síntesis química , Flunitrazepam/metabolismo , Agonistas del GABA/síntesis química , Moduladores del GABA/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Isoflavonas/síntesis química , Isoflavonas/metabolismo , Cinética , Masculino , Potenciales de la Membrana/efectos de los fármacos , Midazolam/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Embarazo , Ratas , Ratas Wistar , Receptores de GABA-A/fisiología , Sinaptosomas/metabolismo , Factores de Tiempo , Tritio , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
In pursuit of a GABA(A) alpha5-subtype-selective inverse agonist to enhance cognition, a series of 6,7-dihydro-2-benzothiophen-4(5H)-ones has been identified as a novel class of GABA(A) receptor ligands. These thiophenes have higher binding affinity for the GABA(A) alpha5 receptor subtype compared to the GABA(A) alpha1, alpha2, and alpha3 subtypes, and several analogues exhibit high GABA(A) alpha5 receptor inverse agonism. 6,6-Dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (43) has been identified as a full inverse agonist at the GABA(A) alpha5 receptor and is functionally selective over the other major GABA(A) receptor subtypes. 43 readily penetrates into the CNS to give selective occupancy of GABA(A) alpha5 receptors. In addition, 43 enhances cognitive performance in rats in the delayed 'matching-to-place' Morris water maze test-a hippocampal-dependent memory task-without the convulsant or proconvulsant activity associated with nonselective, GABA(A) receptor inverse agonists.
Asunto(s)
Cognición/efectos de los fármacos , Agonistas del GABA/síntesis química , Nootrópicos/síntesis química , Receptores de GABA-A/efectos de los fármacos , Tiazoles/síntesis química , Tiofenos/síntesis química , Animales , Encéfalo/metabolismo , Línea Celular , Femenino , Agonistas del GABA/efectos adversos , Agonistas del GABA/farmacología , Hipocampo/fisiología , Humanos , Técnicas In Vitro , Ligandos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Ratones , Nootrópicos/efectos adversos , Nootrópicos/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Subunidades de Proteína , Ensayo de Unión Radioligante , Ratas , Convulsiones/inducido químicamente , Relación Estructura-Actividad , Tiazoles/efectos adversos , Tiazoles/farmacología , Tiofenos/efectos adversos , Tiofenos/farmacología , Xenopus laevisRESUMEN
The synthesis and evaluation of [(11)C]zolpidem, an imidazopyridine with agonist properties at central benzodiazepine receptors, is reported herein. The reaction of desmethylzolpidem with [(11)C] methyl iodide afforded the title compound [(11)C]zolpidem in a yield of 19.19 +/- 3.23% in 41 +/- 2 min in specific activities of 0.995-1.19 Ci/micromol (1.115 +/- 0.105 Ci/micromol) (n = 3; decay corrected, EOB). The amount of radioactivity in the brain after tail vein injection in male Wistar rats was low, and the regional distribution was homogeneous and not consistent with the known distribution of the central benzodiazepine receptors. The frontal cortex/cerebellum ratio was not significantly greater than one (1.007 +/- 0.266 at 5 min) and did not increase from 5 to 40 min post-injection. A PET brain imaging study in one baboon confirmed the results obtained in rats. Therefore, it can be concluded that [(11)C]zolpidem is not a suitable tracer for in vivo visualization of central benzodiazepine receptors.