RESUMO
Glycine transporter type-1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [(11) C]GSK931145, and [(18) F]MK-6577, in baboons. Two baboons were imaged with [(11) C]GSK931145 and [(18) F]MK-6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [(11) C]GSK931145 and [(18) F]MK-6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with â¼ 30% of parent at 30 min post-injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [(18) F]MK-6577 displayed higher uptake and faster kinetics than [(11) C]GSK931145. Time activity curves were well described by the two-tissue compartment model. Regional volume of distribution (VT ) values were higher for [(18) F]MK-6577 than [(11) C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [(18) F]MK-6577 than [(11) C]GSK931145, consistent with higher regional binding potential (BPND ) values of [(18) F]MK-6577 calculated using VT from the baseline scans and non-displaceable distribution volume (VND ) derived from blocking studies. [(18) F]MK-6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [(11) C]GSK931145.
Assuntos
Benzamidas , Radioisótopos de Carbono , Glicinérgicos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Compostos Radiofarmacêuticos , Sulfonamidas , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Mapeamento Encefálico , Radioisótopos de Carbono/farmacocinética , Cromatografia Líquida de Alta Pressão , Avaliação Pré-Clínica de Medicamentos , Feminino , Glicinérgicos/síntese química , Glicinérgicos/química , Glicinérgicos/farmacocinética , Cinética , Modelos Lineares , Imageamento por Ressonância Magnética , Estrutura Molecular , Papio , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
A high-throughput screen targeting the EP(1) receptor identified non-acidic glycine sulfonamide derivative 2a with a pK(i) of 6.2. Analogue synthesis allowed a thorough investigation of the structure-activity relationship (SAR) and led to a 100-fold increase in recombinant potency.
Assuntos
Glicinérgicos/síntese química , Glicinérgicos/farmacologia , Receptores de Prostaglandina E/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Animais , Células CHO , Membrana Celular/metabolismo , Cromatografia Líquida de Alta Pressão , Cricetinae , Cricetulus , Sistema Enzimático do Citocromo P-450/metabolismo , Dinoprostona/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Receptores de Prostaglandina E Subtipo EP1RESUMO
Five synthetic approaches to racemic strychnine (1), with the cobalt-mediated [2 + 2 + 2] cycloaddition of alkynes to indoles as the key step, are described. These include the generation and attempted cyclization of macrocycle 8 and the synthesis of dihydrocarbazoles 15, 22, and 26 and their elaboration to pentacyclic structures via a conjugate addition, dipolar cycloaddition, and propellane-to-spirofused skeletal rearrangement, respectively. Finally, the successful total synthesis of 1 is discussed. The development of a short, highly convergent route (14 steps in the longest linear sequence) is highlighted by the cyclization of enynoylindole 40 with acetylene and the formal intramolecular 1,8-conjugate addition of amine 49 to form pentacycle 50. Numerous attempts toward the formation of the piperidine ring of 1 from vinyl iodide 56 were made and its successful formation via palladium-, nickel-, and radical-mediated processes is described.
Assuntos
Cobalto/química , Estricnina/síntese química , Química Orgânica/métodos , Glicinérgicos/síntese química , Espectroscopia de Ressonância Magnética , Níquel/química , Oxirredução , Paládio/química , Venenos/síntese química , EstereoisomerismoRESUMO
The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.
Assuntos
Glicinérgicos/síntese química , Indóis/síntese química , N-Metilaspartato/antagonistas & inibidores , Animais , Sítios de Ligação , Ácidos Carboxílicos , Glicina , Glicinérgicos/metabolismo , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Indóis/metabolismo , N-Metilaspartato/metabolismo , Ensaio Radioligante , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Quantitative structure-activity relationships of two series of glycine antagonists, pyrido[2,3-b]pyrazines and pyrido[2,3-b]pyrazine N-oxides, was performed using PLS (Projection on Latent Variables) and traditional physico-chemical and topological descriptors. The effect of substitution on the heteroaromatic ring was investigated with the aim of further improving the affinity (expressed as pKi) of these derivatives towards the strychnine-insensitive glycine binding site associated with the NMDA receptor. A significant model was obtained for both series of compounds. Structure-activity implications are discussed.
Assuntos
Glicinérgicos/síntese química , Glicina/antagonistas & inibidores , Fenômenos Químicos , Físico-Química , Interpretação Estatística de Dados , Glicinérgicos/farmacologia , Relação Estrutura-AtividadeRESUMO
A synthetic procedure for the preparation of indole-2,3-dione derivatives 6 as a potential NMDA receptor glycine site antagonist with improved pharmacological profile compared with 2-carboxyindole derivative 5, starting from readily available 3,5-dichloroaniline (7), is described.
Assuntos
Glicinérgicos/síntese química , Hidrazonas/síntese química , Indóis/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Glicinérgicos/farmacologia , Hidrazonas/farmacologia , Indicadores e Reagentes , Indóis/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
The NMDA receptor is an ionotropic receptor complex widely distributed in the central nervous system and its activation, particularly in hypoxic conditions such as stroke, traumatic head injury and hypoglycemia, results in a massive influx of calcium ions into the post-synaptic neurones, leading to cell death through the activation of several neurotoxic cascades. The NMDA receptor is a unique ionotropic receptor complex because its activation requires the simultaneous binding of glutamate and glycine and selective antagonists at the glycine binding site are endowed with a better side-effect profile than competitive NMDA antagonists. Then, considerable efforts have been devoted to find potent and selective ligands, resulting in the identification of several classes of glycine antagonists. The research at Glaxo Wellcome has been aimed at the identification of novel in vivo active glycine antagonists, and led to the synthesis and pharmacological characterization of a number of novel, potent and systemically active compounds belonging to different chemical classes.
Assuntos
Glicinérgicos/síntese química , Glicinérgicos/farmacologia , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Glicinérgicos/química , HumanosRESUMO
A series of analogues of the indole-2-carboxylate GV150526, currently in clinical trials as a potential neuroprotective agent for the control of the cerebral damage after stroke onset, was designed based on previous studies dealing with the electronic features of the north-east region of the glycine binding site associated with the NMDA receptor. In particular, the substitution of the para position of the terminal phenyl ring of GV150526 with suitable hydrophilic groups resulted in the identification of a new class of glycine antagonists. These compounds exhibited nanomolar in vitro affinity to the glycine binding site, high receptor selectivity, and outstanding in vivo potency. In particular, 3-[(E)-2-[(4-ureidomethylphenyl)aminocarbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid was found to be highly effective in the middle cerebral artery occlusion (MCAo) model in the rat, an animal model of focal ischemia, when given both prior to and after the occlusion of the middle cerebral artery. Notably, a significant neuroprotective effect was seen in this model postischaemia, when the administration of this compound was delayed up to 6 h from the occlusion of the middle cerebral artery, further confirming the wide therapeutic window seen for GV150526A.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Glicinérgicos/síntese química , Indóis/química , Indóis/síntese química , Fármacos Neuroprotetores/síntese química , Receptores de Glicina/antagonistas & inibidores , Ureia/análogos & derivados , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Sítios de Ligação/efeitos dos fármacos , Ácidos Carboxílicos , Infarto Cerebral/tratamento farmacológico , Modelos Animais de Doenças , Glicina/metabolismo , Glicinérgicos/farmacologia , Indóis/farmacologia , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Ureia/síntese química , Ureia/farmacologiaRESUMO
Twenty 4,5-dimethylpyrrole-2-carboxylic acids (5a-t) with different 2-carbamoylvinyl chains in position 3 were prepared to further investigate the relationships between structure and in vitro affinity for the strychnine-insensitive glycine-binding site. None of these compounds was superior to (E)-3-(N-phenyl-2-carbamoylvinyl)-4,5-dimethylpyrrole-2-carb oxylic acid III (pKi = 6.70), which was taken as a reference standard, but overall the results obtained indicate that the N-phenyl-2-carbamoylvinyl substituent of III may be replaced with the N-(1-adamantyl)-2-carbamoylvinyl group as in 5h (pKi = 6.20) without considerable loss of affinity. This finding adds to previous knowledge.
Assuntos
Ácidos Carboxílicos/síntese química , Glicinérgicos/síntese química , Pirróis/síntese química , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Glicinérgicos/química , Glicinérgicos/metabolismo , Técnicas In Vitro , Ligantes , Pirróis/química , Pirróis/metabolismo , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Estricnina/farmacologia , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismoRESUMO
The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi = 7.95 +/- 0.01) and the 4-bromo-5-methyl 6j (pKi = 7.24 +/- 0.01) and 4,5-dimethyl 6g (pKi = 6.70 +/- 0.03) analogues were the most active compounds of the series. Qualitative structure-activity analysis points to a negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced by halo-substituents. QSAR analysis by the Hansch descriptors F, R, pi, and MR, on a subset of compounds with pKi > or = 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions. 6g was found to be a full antagonist (alpha = 0; enhancement of the [3H]TCP binding). The in vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions in mice by both the i.v. and po routes; 6w was the most active compound (ED50 = 3 x 10(-3) (0.8-10) g/kg, i.v. and 30 x 10(-3) (4.5-61) g/kg, p.o.). The results of this study indicate that the 3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine antagonists.
Assuntos
Acrilamidas , Anticonvulsivantes , Glicinérgicos , Pirróis , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Acrilamidas/síntese química , Acrilamidas/química , Acrilamidas/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/ultraestrutura , Glicinérgicos/síntese química , Glicinérgicos/química , Glicinérgicos/farmacologia , Indóis/química , Indóis/farmacologia , Camundongos , Modelos Moleculares , N-Metilaspartato/toxicidade , Pirróis/síntese química , Pirróis/química , Pirróis/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsões/induzido quimicamente , Relação Estrutura-Atividade , Sinapses/efeitos dos fármacos , Sinapses/metabolismoRESUMO
A series of indole-2-carboxylates bearing suitable chains at the C-3 position of the indole nucleus was synthesized and evaluated in terms of in vitro affinity using [3H]glycine binding assay and in vivo potency by inhibition of convulsions induced by N-methyl-D-aspartate (NMDA) in mice. 3-[2-[(Phenylamino)carbonyl]ethenyl]-4,6-dichloroindole-2-carboxyl ic acid (8) was an antagonist at the strychnine-insensitive glycine binding site (noncompetitive inhibition of the binding of [3H]TCP, pA2 = 8.1) displaying nanomolar affinity for the glycine binding site (pKi = 8.5), coupled with high glutamate receptor selectivity (> 1000-fold relative to the affinity at the NMDA, AMPA, and kainate binding sites). This indole derivative inhibited convulsions induced by NMDA in mice, when administered by both iv and po routes (ED50 = 0.06 and 6 mg/kg, respectively). The effect of the substituents on the terminal phenyl ring of the C-3 side chain was investigated. QSAR analysis suggested that the pKi value decreases with lipophilicity and steric bulk of substituents and increases with the electron donor resonance effect of the groups present in the para position of the terminal phenyl ring. According to these results the terminal phenyl ring of the C-3 side chain should lie in a nonhydrophobic pocket of limited size, refining the proposed pharmacophore model of the glycine binding site associated with the NMDA receptor.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Glicinérgicos/farmacologia , Glicina/antagonistas & inibidores , Indóis/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Ácidos Carboxílicos , Córtex Cerebral/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/metabolismo , Glicina/metabolismo , Glicinérgicos/síntese química , Glicinérgicos/química , Glicinérgicos/metabolismo , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Espectroscopia de Ressonância Magnética , Camundongos , Estrutura Molecular , N-Metilaspartato/farmacologia , Ratos , Receptores de Glutamato/metabolismo , Relação Estrutura-Atividade , Estricnina/farmacologiaRESUMO
This paper describes the synthesis of beta-(dialkylaminomethyl)-gamma- butyrolactones (6 and 15) and their tetrahydrofuran analogs 7 and 16. Their convulsant activity was studied on mice and could display an antiGABAergic component, but, unlike the alpha-(dialkylaminomethyl)- gamma-butyrolactones, no antiglycinergic component was detected. The possibility of an activation of the glutamatergic receptors (NMDA), by indirect stimulation of their glycinergic site, by the tetrahydrofurans analogs 7 could be considered. These compounds exhibited, at low doses (1/3 to 1/20 of their convulsant doses), an anticonvulsant action in the maximal electroshock test and this is in agreement with the abovementioned possibility.