RESUMO
INTRODUCTION: A radioligand for measuring the density of corticotropin-releasing factor subtype-1 receptors (CRF1 receptors) in living animal and human brain with positron emission tomography (PET) would be a useful tool for neuropsychiatric investigations and the development of drugs intended to interact with this target. This study was aimed at discovery of such a radioligand from a group of CRF1 receptor ligands based on a core 3-(phenylamino)-pyrazin-2(1H)-one scaffold. METHODS: CRF1 receptor ligands were selected for development as possible PET radioligands based on their binding potency at CRF1 receptors (displacement of [(125)I]CRF from rat cortical membranes), measured lipophilicity, autoradiographic binding profile in rat and rhesus monkey brain sections, rat biodistribution, and suitability for radiolabeling with carbon-11 or fluorine-18. Two identified candidates (BMS-721313 and BMS-732098) were labeled with fluorine-18. A third candidate (BMS-709460) was labeled with carbon-11 and all three radioligands were evaluated in PET experiments in rhesus monkey. CRF1 receptor density (Bmax) was assessed in rhesus brain cortical and cerebellum membranes with the CRF1 receptor ligand, [(3)H]BMS-728300. RESULTS: The three ligands selected for development showed high binding affinity (IC50 values, 0.3-8nM) at CRF1 receptors and moderate lipophilicity (LogD, 2.8-4.4). [(3)H]BMS-728300 and the two (18)F-labeled ligands showed region-specific binding in rat and rhesus monkey brain autoradiography, namely higher binding density in the frontal and limbic cortex, and cerebellum than in thalamus and brainstem. CRF1 receptor Bmax in rhesus brain was found to be 50-120 fmol/mg protein across cortical regions and cerebellum. PET experiments in rhesus monkey showed that the radioligands [(18)F]BMS-721313, [(18)F]BMS-732098 and [(11)C]BMS-709460 gave acceptably high brain radioactivity uptake but no indication of the specific binding as seen in vitro. CONCLUSIONS: Candidate CRF1 receptor PET radioligands were identified but none proved to be effective for imaging monkey brain CRF1 receptors. Higher affinity radioligands are likely required for successful PET imaging of CRF1 receptors.
Assuntos
Tomografia por Emissão de Pósitrons/métodos , Pirazinas/metabolismo , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Técnicas de Química Sintética , Ligantes , Macaca mulatta , Masculino , Pirazinas/síntese química , Pirazinas/química , Radioquímica , Ratos , Distribuição TecidualRESUMO
Racemic 5-(trans-2-aminomethylcyclopropyl)indoles, 5-(trans-2-aminomethylcyclopentyl) indoles, and 5-(cis-2-aminomethylcyclopentyl)indoles were synthesized and evaluated as selective serotonin reuptake inhibitors. These analogs followed SAR trends similar to those previously reported for 3-cycloalkyl substituted indoles. The most potent analogs exhibited single digit nanomolar inhibition at the human serotonin transporter but were 10-fold less active than the previously reported compounds.
Assuntos
Metilaminas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Metilaminas/síntese química , Metilaminas/química , Conformação Molecular , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A series of pyrazinones were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients are discussed herein.
Assuntos
Tomografia por Emissão de Pósitrons , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Encéfalo , Humanos , Estrutura Molecular , Pirazinas/química , Ratos , Receptores de Hormônio Liberador da Corticotropina/químicaRESUMO
Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [(18)F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments.
Assuntos
Compostos de Anilina/química , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Pirazinas/química , Pirazóis/química , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Flúor/sangue , Imageamento Tridimensional , Estrutura Molecular , Pirazóis/metabolismo , Ratos , Distribuição TecidualRESUMO
A series of N-fluoroalkyl-8-(6-methoxy-2-methylpyridin-3-yl)-2,7-dimethyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines were prepared and evaluated as potential CRF(1)R PET imaging agents. Optimization of their CRF(1)R binding potencies and octanol-phosphate buffer phase distribution coefficients resulted in discovery of analog 7e (IC(50)=6.5 nM, logD=3.5).
Assuntos
Aminas/química , Pirazóis/química , Receptores de Hormônio Liberador da Corticotropina/química , Triazinas/química , Aminas/síntese química , Cristalografia por Raios X , Conformação Molecular , Tomografia por Emissão de Pósitrons , Pirazóis/síntese química , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Triazinas/síntese químicaRESUMO
A series of conformationally restricted homotryptamines has been synthesized and shown to be potent inhibitors of hSERT. Conformational restriction of the homotryptamine side chain was attained by the insertion of a cyclopentyl ring, with the indole ring and the terminal dialkylamino group occupying the 1- and 3-positions, respectively. Nitrile and fluoro substitutions at the indole 5-position gave highest hSERT potency. Preferred cyclopentane ring stereochemistry in both series was cis (1S,3R for 5-CN compound 8a, 1R,3S for 5-F compound 9a). High hSERT binding affinity was observed for 8a and 9a (0.22 and 0.63 nM, respectively). The corresponding trans isomers were 4-9 times less potent. 8a, dosed at 1 and 3 mg/kg po, produced a robust, dose-dependent increase in extracellular serotonin in the frontal cortex of rats, similar to that induced by paroxetine at 5 mg/kg, po. By contrast, 9a did not produce a significant increase in extracellular serotonin in rat frontal cortex at 3 mg/kg po due to relatively low brain and plasma levels.
Assuntos
Ciclopentanos/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Disponibilidade Biológica , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Ciclopentanos/química , Ciclopentanos/farmacologia , Espaço Extracelular/metabolismo , Humanos , Microdiálise , Modelos Moleculares , Conformação Molecular , Ratos , Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
Substituted 1-tosyl-3-vinylindoles undergo [3+2] dipolar cycloaddition with cyclic nitrones to afford substituted isoxazoles in good yield and high diastereoselectivity. The cycloadducts were readily converted in 4 steps into ring constrained homotryptamine analogs. These analogs exhibited excellent binding affinity for the human serotonin transporter (hSERT). Indoles bearing a 5-cyano group and a pendent ethyl(tetrahydroisoquinoline) moiety at the 3-position displayed the best potency for hSERT and high selectivity versus hDAT and hNET.
Assuntos
Indóis/síntese química , Indóis/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/síntese química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptaminas/síntese química , Triptaminas/metabolismo , Linhagem Celular , Cristalografia por Raios X , Humanos , Ligação Proteica/fisiologiaRESUMO
Detailed metabolic characterization of 8, an earlier lead pyrazinone-based corticotropin-releasing factor-1 (CRF(1)) receptor antagonist, revealed that this compound formed significant levels of reactive metabolites, as measured by in vivo and in vitro biotransformation studies. This was of particular concern due to the body of evidence suggesting that reactive metabolites may be involved in idiosyncratic drug reactions. Further optimization of the structure-activity relationships and in vivo properties of pyrazinone-based CRF(1) receptor antagonists and studies to assess the formation of reactive metabolites led to the discovery of 19e, a high affinity CRF(1) receptor antagonist (IC(50) = 0.86 nM) wherein GSH adducts were estimated to be only 0.1% of the total amount of drug-related material excreted through bile and urine, indicating low levels of reactive metabolite formation in vivo. A novel 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine group in 19e contributed to the potency and improved in vivo properties of this compound and related analogues. 19e had excellent pharmacokinetic properties in rats and dogs and showed efficacy in the defensive withdrawal model of anxiety in rats. The lowest efficacious dose was 1.8 mg/kg. The results of a two-week rat safety study with 19e indicated that this compound was well-tolerated.
Assuntos
Pirazinas/metabolismo , Pirazinas/farmacologia , Piridinas/metabolismo , Piridinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Masculino , Pirazinas/administração & dosagem , Pirazinas/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , RatosRESUMO
A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF(1)) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF(1) receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC(50) = 1.0 nM) and selective CRF(1) receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.
Assuntos
Pirazinas/farmacologia , Pirazinas/farmacocinética , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Humanos , Concentração Inibidora 50 , Masculino , Taxa de Depuração Metabólica , Pirazinas/química , Pirazinas/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismoRESUMO
Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.
Assuntos
Pirazinas/química , Pirazinas/farmacologia , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Pirazinas/síntese química , Pirazinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A series of racemic 3-(trans-2-aminomethylcyclopentyl)indoles was synthesized and found to have potent binding to the human serotonin transporter (hSERT). The most active analog was synthesized stereospecifically and the active enantiomer was shown to have high affinity binding to hSERT.
Assuntos
Indóis/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Animais , Antidepressivos/química , Química Farmacêutica/métodos , Ciclopentanos/química , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Ligação Proteica , Ratos , Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A series of hybrid molecules containing the cyclopropylmethylamino side chain found in homotryptamine (1S,2S)-2c and an isosteric heteroaryl or naphthyl core were prepared and their binding affinities for the human serotonin transporter determined. The most potent isosteres were CN-substituted naphthalenes. These results demonstrate that isosteric aromatic cores which lack an H-bond donor site may be substituted for the indole nucleus without substantial loss in hSERT binding.
Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Compostos Heterocíclicos/síntese química , Humanos , Concentração Inibidora 50 , Conformação Molecular , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Relação Estrutura-AtividadeRESUMO
A series of indole tetrahydropyridine and indole cyclohexenylamines was prepared, and their binding affinities at the human serotonin transporter (SERT) were determined. In particular, a nitrile substituent at the C5 position of the indole ring gave potent SERT activity. The stereochemistry of the N,N-dimethylamine substituent was determined for the most potent indole cyclohexenylamine, 6a. The enantiomers of 6a were energy minimized and compared to other conformationally restricted SSRIs. Compound 6a was found to give a dose-response similar to the SSRI fluoxetine in microdialysis studies in rats.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Triptaminas/química , Animais , Cicloexenos/síntese química , Cicloexenos/química , Cicloexenos/farmacologia , Fluoxetina/química , Fluoxetina/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Microdiálise , Conformação Molecular , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/síntese químicaRESUMO
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions of the indole ring gave high affinity for hSERT, and the preferred cyclopropane stereochemistry was determined to be (1S,2S)-trans. The cis-cyclopropanes had 20- to 30-fold less affinity than the trans, and the preferred cis stereochemistry was (1R,2S)-cis. Substitution of the indole N-1 position with methyl or ethyl groups gave a 10- to 30-fold decrease in affinity for hSERT, suggesting either a hydrogen-bonding interaction or limited steric tolerance in the region of the indole nitrogen. Compound (+)-12a demonstrated potent hSERT binding (Ki = 0.18 nM) in vitro and was more than 1000-fold less potent at hDAT, hNET, 5-HT1A, and 5-HT6. In vivo, (+)-12a produced robust, dose-dependent increases in extracellular serotonin in rat frontal cortex typical of a selective serotonin reuptake inhibitor. The maximal response produced by (+)-12a was similar to that of fluoxetine but at an approximately 10-fold lower dose.
Assuntos
Ciclopropanos/síntese química , Indóis/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Triptaminas/síntese química , Animais , Cristalografia por Raios X , Ciclopropanos/química , Ciclopropanos/farmacologia , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Indóis/química , Indóis/farmacologia , Microdiálise , Modelos Moleculares , Conformação Molecular , Ensaio Radioligante , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Triptaminas/química , Triptaminas/farmacologiaRESUMO
[reaction: see text] Substituted 1-tosyl-3-vinylindoles undergo catalytic asymmetric cyclopropanation with ethyl- and tert-butyldiazoacetate to afford N-protected trans-2-(indol-3-yl)-1-cyclopropanecarboxylic esters in good yield and high enantiomeric excess (81-88% ee). The resulting cycloadducts are demonstrated to be useful intermediates for the synthesis of conformationally restricted, homotryptamine-like analogues such as BMS-505130.
Assuntos
Compostos Azo/química , Ciclopropanos/síntese química , Indóis/química , Indóis/síntese química , Compostos de Tosil/química , Triptaminas/síntese química , Compostos de Vinila/química , Acetatos/química , Catálise , Ciclização , Estrutura MolecularRESUMO
BMS-505130 is a potent and selective serotonin transport inhibitor; K(i) for binding to the serotonin transporter = 0.18 nM (K(i) values for binding to the norepinephrine and dopamine transporters = 4.6 and 2.1 microM, respectively). In platelet serotonin uptake studies BMS-505130 (5 mg/kg, p.o.) produced a robust inhibition of serotonin uptake. In microdialysis studies oral dosing with BMS-505130 produced a dose-dependent increase in cortical serotonin levels that reached a maximal effect of 200% above baseline at a dose of 1 mg/kg, p.o.; the peak serotonin response was transient in nature. Following oral administration, peak plasma concentrations of BMS-505130 reached Tmax at 1.6 +/- 0.7 h and then declined to concentrations <10% of Cmax within the following 6 h; plasma half-life following i.v. dosing was 0.46 +/- 0.02 h. Parallel microdialysis and pharmacokinetic studies revealed that changes in serotonin levels in the cortex mirrored changes in the brain concentration of BMS-505130. In a behavioral assay known to be sensitive to selective serotonin reuptake inhibitors (SSRIs), mouse tail suspension, BMS-505130 produced a robust response after either oral or intraperitoneal dosing. BMS-505130 exhibits a pharmacological, neurochemical and behavioral profile consistent with a potent SSRI. Moreover, BMS-505130's short half-life may be advantageous for the treatment of premature ejaculation where an acute effect to delay ejaculation followed by a relatively rapid fall in SSRI plasma concentrations might be desirable.
Assuntos
Elevação dos Membros Posteriores/métodos , Indóis/farmacocinética , Glicoproteínas de Membrana/antagonistas & inibidores , Moduladores de Transporte de Membrana , Proteínas de Membrana Transportadoras/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Administração Oral , Animais , Células CHO , Linhagem Celular , Cricetinae , Ciclopropanos , Cães , Relação Dose-Resposta a Droga , Humanos , Indóis/administração & dosagem , Indóis/farmacologia , Masculino , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
A series of N,N-dimethylhomotryptamines was prepared and their binding affinities at the serotonin transporter (SERT) were determined. Compounds possessing an electron withdrawing substituent at the C5-position of the indole nucleus were found to be potent SSRIs. Initial attempts at conformational restriction of the propylamine sidechain by incorporation of a quinuclidine bicyclic structure did not improve binding affinity at SERT.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Triptaminas/química , Triptaminas/farmacologia , Linhagem Celular , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Modelos Químicos , Estrutura Molecular , Proteínas do Tecido Nervoso/metabolismo , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de SerotoninaRESUMO
Conformationally constrained aryl cyclohexanes and cyclohexenes based on aryl cyclohexanols 1 were prepared. Locking the aryl ring in plane with the cyclohexane moiety provided potent SSRIs 3. Conversely, fixing the aryl ring perpendicular to the cyclohexane ring via a spiro lactone provided balanced 5-HT1A antagonists with mid-nanomolar range SSRI potency (compounds 2).
Assuntos
Receptor 5-HT1A de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Serotonina/metabolismo , Ligantes , Conformação MolecularRESUMO
A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.
Assuntos
Fenômenos Cronobiológicos/fisiologia , Fluorenos/química , Melatonina/metabolismo , Amidas/síntese química , Amidas/farmacologia , Animais , Sítios de Ligação , Relação Dose-Resposta a Droga , Humanos , Camundongos , Células NIH 3T3 , Ensaio Radioligante , Ratos , Receptores de Melatonina/metabolismo , Relação Estrutura-AtividadeRESUMO
The present studies have identified a series of aminotriazines as novel 5-HT(7) receptor antagonists. Compounds 10 and 17 have high affinity for the 5-HT(7) receptor and do not bind to either the 5-HT(2C) or 5-HT(6) receptors. These compounds produce no agonist effects by themselves, and shift the dose-response curve of 5-CT to the right in the manner of an antagonist.