RESUMEN
A novel 4-aminocyclopentapyrrolidine series of N-type Ca(2+) channel blockers have been discovered. Enantioselective synthesis of the 4-aminocyclopentapyrrolidines was enabled using N-tert-butyl sulfinamide chemistry. SAR studies demonstrate selectivity over L-type Ca(2+) channels. N-type Ca(2+) channel blockade was confirmed using electrophysiological recording techniques. Compound 25 is an N-type Ca(2+) channel blocker that produces antinociception in inflammatory and nociceptive pain models without exhibiting cardiovascular or motor liabilities.
Asunto(s)
Acetamidas/síntesis química , Analgésicos/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo N/química , Pirrolidinas/química , Pirrolidinas/síntesis química , Acetamidas/farmacología , Acetamidas/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Conducta Animal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Modelos Animales de Enfermedad , Masculino , Dolor/tratamiento farmacológico , Pirrolidinas/farmacología , Pirrolidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A novel series of diphenyl lactam containing calcium channel blockers is described. Extensive SAR studies resulted in compounds with low molar activity and good plasma exposure after oral dosing. Compounds 2, 6 and 7 demonstrated significant efficacy in the capsaicin model of secondary hyperalgesia following oral administration.
Asunto(s)
Compuestos de Bifenilo/síntesis química , Bloqueadores de los Canales de Calcio/síntesis química , Canales de Calcio Tipo N/metabolismo , Descubrimiento de Drogas , Lactamas/síntesis química , Administración Oral , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Concentración 50 Inhibidora , Lactamas/química , Lactamas/farmacocinética , Estructura Molecular , Piperazinas/química , Ratas , SolubilidadRESUMEN
Blockade of voltage-gated Ca²âº channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²âº channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC50=0.8 µM and 1.4 µM, respectively) and T-type (IC50=4.6 µM and 1.2 µM, respectively) Ca²âº channels in FLIPR based Ca²âº flux assays. A-686085 also potently blocked L-type Ca²âº channels (EC50=0.6 µM), however, A-1048400 was much less active in blocking this channel (EC50=28 µM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC50=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²âº currents in rat dorsal root ganglion neurons (IC50=3.0 µM and 1.6 µM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²âº channels coupled with pharmacological selectivity vs. L-type Ca²âº channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function.
Asunto(s)
Analgésicos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Hemodinámica/fisiología , Neuronas/fisiología , Dimensión del Dolor , Piperidonas/administración & dosificación , Piperidonas/química , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Hemodinámica/efectos de los fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-DawleyRESUMEN
High-throughput screening (HTS) identified benzothiazole analogue 3 as a potent fatty acid amide hydrolase (FAAH) inhibitor. Structure-activity relationship (SAR) studies indicated that the sulfonyl group, the piperidine ring and benzothiazole were the key components to their activity, with 16j being the most potent analogue in this series. Time-dependent preincubation study of compound 3 was consistent with it being a reversible inhibitor. Activity-based protein-profiling (ABPP) evaluation of 3 in rat tissues revealed that it had exceptional selectivity and no off-target activity with respect to other serine hydrolases. Molecular shape overlay of 3 with a known FAAH inhibitor indicated that these compounds might act as transition-state analogues, forming putative hydrogen bonds with catalytic residues and mimicking the charge distribution of the tetrahedral transition state. The modeling study also indicated that hydrophobic interactions of the benzothiazole ring with the enzyme contributed to its extraordinary potency. These compounds may provide useful tools for the study of FAAH and the endocannabinoid system.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Benzotiazoles/síntesis química , Benzotiazoles/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Amidohidrolasas/metabolismo , Animales , Benzotiazoles/química , Cristalografía por Rayos X , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Especificidad de Órganos/efectos de los fármacos , Unión Proteica , Ratas , Relación Estructura-Actividad , Factores de TiempoRESUMEN
Potent small molecule antagonists for the PAC(1)-R have been discovered. Previously known antagonists for the PAC(1)-R were slightly truncated peptide ligands. The hydrazides reported here are the first small molecule antagonists ever reported for this class B GPCR.
Asunto(s)
Hidrazinas/química , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/antagonistas & inhibidores , Calcio/metabolismo , Células Cultivadas , Humanos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Ensayo de Unión Radioligante , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Relación Estructura-ActividadRESUMEN
Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu1 receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED50s of 10, 50, 50, and 65 micromol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu1 receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu1 receptor antagonists as novel analgesics.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Dolor Postoperatorio/prevención & control , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos no Narcóticos/química , Animales , Calcio/metabolismo , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cerebelo/citología , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Dimetilaminas/química , Dimetilaminas/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/química , Conducta Exploratoria/efectos de los fármacos , Fluorometría/métodos , Glicina/análogos & derivados , Glicina/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Miembro Posterior/cirugía , Masculino , Estructura Molecular , Morfina/farmacología , Dolor Postoperatorio/etiología , Piridinas/química , Piridinas/farmacología , Pirimidinonas/química , Pirimidinonas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Resorcinoles/farmacología , Prueba de Desempeño de Rotación con Aceleración Constante/métodos , Tiofenos/química , Tiofenos/farmacología , TritioRESUMEN
Our HTS effort yielded a preferential mGluR1 pyrimidinone antagonist 1 with lead-like characteristics. Rapid hit to lead (HTL) study identified compounds with improved functional activity and selectivity such as 1b with little improvements in ADME properties. Addition of an aminosulfonyl group on the N-1 aromatic ring led to 2f, a compound with similar in vitro biochemical profiles as those of 1b but drastically improved in vitro ADME properties. These improvements were paralleled by rat PK study characterized by low clearance and quantitative bioavailability. Compound 2f represented a true lead-like molecule that is amenable for further lead optimization (LO) evaluation.
Asunto(s)
Pirazoles/química , Piridinas/química , Pirimidinonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Pirimidinonas/química , Pirimidinonas/farmacocinética , RatasRESUMEN
A series of non-nucleoside adenosine kinase (AK) inhibitors is reported. These inhibitors originated from the modification of 5-(3-bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine (ABT-702). The identification of a linker that would approximate the spatial arrangement found between the pyrimidine ring and the aryl group at C(7) in ABT-702 was a key element in this modification. A search of potential linkers led to the discovery of an acetylene moiety as a suitable scaffold. It was hypothesized that the aryl acetylenes, ABT-702, and adenosine bound to the active site of AK (closed form) in a similar manner with respect to the orientation of the heterocyclic base. Although potent acetylene analogs were discovered based on this assumption, an X-ray crystal structure of 5-(4-dimethylaminophenyl)-6-(6-morpholin-4-ylpyridin-3-ylethynyl)pyrimidin-4-ylamine (16a) revealed a binding orientation contrary to adenosine. In addition, this compound bound tightly to a unique open conformation of AK. The structure-activity relationships and unique ligand orientation and protein conformation are discussed.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacología , Adenosina Quinasa/química , Animales , Sitios de Unión , Cristalografía por Rayos X , Concentración 50 Inhibidora , Ratones , Morfolinas , Unión Proteica , Conformación Proteica , Pirimidinas/síntesis química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Adenosine kinase (AK) is an enzyme responsible for converting endogenous adenosine (ADO) to adenosine monophosphate (AMP) in an adenosine triphosphate- (ATP-) dependent manner. The structure of AK consists of two domains, the first a large alpha/beta Rossmann-like nucleotide binding domain that forms the ATP binding site, and a smaller mixed alpha/beta domain, which, in combination with the larger domain, forms the ADO binding site and the site of phosphoryl transfer. AK inhibitors have been under investigation as antinociceptive, antiinflammatory, and anticonvulsant as well as antiinfective agents. In this work, we report the structures of AK in complex with two classes of inhibitors: the first, ADO-like, and the second, a novel alkynylpyrimidine series. The two classes of structures, which contain structurally similar substituents, reveal distinct binding modes in which the AK structure accommodates the inhibitor classes by a 30 degrees rotation of the small domain relative to the large domain. This change in binding mode stabilizes an open and a closed intermediate structural state and provide structural insight into the transition required for catalysis. This results in a significant rearrangement of both the protein active site and the orientation of the alkynylpyrimidine ligand when compared to the observed orientation of nucleosidic inhibitors or substrates.
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Adenosina Quinasa/química , Inhibidores Enzimáticos/química , Morfolinas/química , Pirimidinas/química , Tubercidina/análogos & derivados , Animales , Sitios de Unión , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Estructura Molecular , Unión Proteica , Conformación Proteica , Toxoplasma/enzimología , Tubercidina/químicaRESUMEN
The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
Asunto(s)
Benzamidas/síntesis química , Óxidos N-Cíclicos/síntesis química , Disfunción Eréctil/tratamiento farmacológico , Receptores de Dopamina D4/agonistas , Potenciales de Acción , Administración Oral , Animales , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Línea Celular , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/farmacología , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/fisiología , Haplorrinos , Humanos , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Ramos Subendocárdicos/efectos de los fármacos , Ramos Subendocárdicos/fisiología , Ratas , Relación Estructura-ActividadRESUMEN
A gram scale synthesis of the glucuronide metabolite of ABT-724 is reported. Glycosidic coupling between a trichloroacetimidate glucuronyl donor and a Cbz-protected hydroxypyridylpiperazine glycosyl acceptor is the key step in the synthesis, since attempts to directly glucuronidate the aglycon, aglycon derivatives, and other truncated glycosyl acceptors were unsuccessful. The route was used to produce 2.1 g of metabolite in eight steps from 2-chloro-5-hydroxypyridine in 21% overall yield.
Asunto(s)
Bencimidazoles/química , Glucurónidos/química , Glucurónidos/síntesis química , Piperazinas/química , Piridinas/química , Bencimidazoles/metabolismo , Agonistas de Dopamina/química , Agonistas de Dopamina/metabolismo , Ésteres/química , Ésteres/metabolismo , Glucurónidos/metabolismo , Estructura Molecular , Piperazinas/metabolismo , Piridinas/metabolismoRESUMEN
A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Oximas/farmacología , Piperazinas/farmacología , Receptores de Dopamina D4/agonistas , Animales , Benzamidas/química , Benzamidas/farmacología , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Hurones , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Oximas/síntesis química , Oximas/química , Piperazinas/síntesis química , Piperazinas/química , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have discovered a novel, potent, and selective triazafluorenone series of metabotropic glutamate receptor 1 (mGluR1) antagonists with efficacy in various rat pain models. Pharmacokinetic and pharmacodynamic profiles of these triazafluorenone analogs revealed that brain/plasma ratios of these mGluR1 antagonists were important to achieve efficacy in neuropathic pain models. This correlation could be used to guide our in vivo SAR (structure-activity relationship) modification. For example, compound 4a has a brain/plasma ratio of 0.34, demonstrating only moderate efficacy in neuropathic pain models. On the other hand, antagonist 4b with a brain/plasma ratio of 2.70 was fully efficacious in neuropathic pain models.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Encéfalo/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Dolor/tratamiento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Compuestos Aza/sangre , Compuestos Aza/química , Encéfalo/metabolismo , Línea Celular , Humanos , Modelos Animales , Estructura Molecular , Dolor/metabolismo , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The dopamine D4 receptor has been investigated for its potential role in several CNS disorders, notably schizophrenia and more recently, erectile dysfunction. Whereas studies have investigated dopamine D4 receptor-mediated signaling in vitro, there have been few, if any, attempts to identify dopamine D4 receptor signal transduction pathways in vivo. In the present studies, the selective dopamine D4 agonist PD168077 induces c-Fos expression and extracellular signal regulated kinase (ERK) phosphorylation in the hypothalamic paraventricular nucleus (PVN), a site known to regulate proerectile activity. The selective dopamine D4 receptor antagonist A-381393 blocked both c-Fos expression and ERK1/2 phosphorylation produced by PD168077. In addition, PD168077-induced ERK1/2 phosphorylation was prevented by SL327, an inhibitor of ERK1/2 phosphorylation. Interestingly, treatment with A-381393 alone significantly reduced the amount of Fos immunoreactivity as compared to basal expression observed in vehicle-treated controls. Dopamine D4 receptor and c-Fos coexpression in the PVN was observed using double immunohistochemical labeling, suggesting that PD168077-induced signaling may result from direct dopamine D4 receptor activation. Our results demonstrate functional dopamine D4 receptor expression and natural coupling in the PVN linked to signal transduction pathways that include immediate early gene and MAP kinase activation. Further, the ability of the selective dopamine D4 antagonist A-381393 alone to reduce c-Fos expression below control levels may imply the presence of a tonic dopamine D4 receptor activation under basal conditions in vivo. These findings provide additional evidence that the PVN may be a site of dopamine D4 receptor-mediated proerectile activity.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Genes fos/fisiología , Núcleo Hipotalámico Paraventricular/metabolismo , Receptores de Dopamina D4/fisiología , Transducción de Señal/fisiología , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/farmacología , Animales , Benzamidas/farmacología , Bencimidazoles/farmacología , Recuento de Células/métodos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Expresión Génica/efectos de los fármacos , Inmunohistoquímica/métodos , Masculino , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inhibidores , Factores de TiempoRESUMEN
SAR (structure-activity relationship) studies of triazafluorenone derivatives as potent mGluR1 antagonists are described. The triazafluorenone derivatives are non-amino acid derivatives and noncompetitive mGluR1 antagonists that bind at a putative allosteric recognition site located within the seven-transmembrane domain of the receptor. These triazafluorenone derivatives are potent, selective, and systemically active mGluR1 antagonists. Compound 1n, for example, was a very potent mGluR1 antagonist (IC50 = 3 nM) and demonstrated full efficacy in various in vivo animal pain models.
Asunto(s)
Analgésicos/síntesis química , Compuestos Aza/síntesis química , Fluorenos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos/química , Analgésicos/farmacología , Animales , Compuestos Aza/química , Compuestos Aza/farmacología , Calcio/metabolismo , Línea Celular , Cerebelo/metabolismo , Fluorenos/química , Fluorenos/farmacología , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Masculino , Dimensión del Dolor , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.
Asunto(s)
Ácidos/farmacología , Amilorida/análogos & derivados , Ganglios Espinales/citología , Proteínas de la Membrana/efectos de los fármacos , Proteínas del Tejido Nervioso/efectos de los fármacos , Neuronas/efectos de los fármacos , Canales de Sodio/efectos de los fármacos , Canales Iónicos Sensibles al Ácido , Amilorida/farmacología , Amilorida/uso terapéutico , Animales , Recuento de Células/métodos , Tamaño de la Célula , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Adyuvante de Freund , Concentración de Iones de Hidrógeno , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Proteínas de la Membrana/clasificación , Naftalenos/farmacología , Naftalenos/uso terapéutico , Proteínas del Tejido Nervioso/clasificación , Dimensión del Dolor/métodos , Umbral del Dolor/efectos de los fármacos , Dolor Postoperatorio/inducido químicamente , Dolor Postoperatorio/dietoterapia , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Sprague-Dawley , Canales de Sodio/clasificaciónRESUMEN
2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393) was identified as a potent dopamine D4 receptor antagonist with excellent receptor selectivity. [3H]-spiperone competition binding assays showed that A-381393 potently bound to membrane from cells expressing recombinant human dopamine D4.4 receptor (Ki=1.5 nM), which was 20-fold higher than that of clozapine (Ki=30.4 nM). A-381393 exhibited highly selective binding for the dopamine D4.4 receptor (>2700-fold) when compared to D1, D2, D3 and D5 dopamine receptors. Furthermore, in comparison to clozapine and L-745870, A-381393 exhibits better receptor selectivity, showing no affinity up to 10 microM for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT2A (Ki=370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-gamma-S binding assay and 1 microM dopamine induced-Ca2+ flux in human dopamine D4.4 receptor expressing cells, but not in human dopamine D2L or D3 receptor cells. In contrast to L-745870, A-381393 did not exhibit any significant intrinsic activity in a D4.4 receptor. In vivo, A-381393 has good brain penetration after subcutaneous administration. A-381393 inhibited penile erection induced by the selective D4 agonist PD168077 in conscious rats. Thus, A-381393 is a novel selective D4 antagonist that will enhance the ability to study dopamine D4 receptors both in vitro and in vivo.
Asunto(s)
Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Animales , Benzamidas/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Unión Competitiva/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Clozapina/farmacocinética , Dopamina/metabolismo , Antagonistas de Dopamina/química , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Interacciones Farmacológicas , Europio/farmacocinética , Fluorometría/métodos , Antagonistas del GABA/farmacocinética , Guanosina Trifosfato/farmacocinética , Humanos , Masculino , Erección Peniana/efectos de los fármacos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Piperazinas/farmacología , Piridinas/farmacocinética , Pirroles/farmacocinética , Ensayo de Unión Radioligante/métodos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Espiperona/farmacocinética , Factores de Tiempo , Tritio/farmacocinéticaRESUMEN
4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).
Asunto(s)
Adenosina Quinasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Morfolinas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Morfolinas/química , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A series of 3-aryl piperidine analogs with 2-piperidinoalkylamino or 2-piperidinoalkyloxy fused bicyclic rings were prepared and found to be potent and efficacious human dopamine D4 agonists. The synthesis and structure-activity relationship (SAR) studies that led to the identification of these compounds are discussed.
Asunto(s)
Agonistas de Dopamina/síntesis química , Agonistas de Dopamina/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores de Dopamina D2/agonistas , Línea Celular , Agonistas de Dopamina/química , Humanos , Ligandos , Estructura Molecular , Piperidinas/síntesis química , Receptores de Dopamina D4 , Relación Estructura-ActividadRESUMEN
The first selective dopamine D4 agonist radioligand is described. The synthesis of these piperazine radioligands relied on the transformation of brominated precursors 4a and 4b with tritium gas in the presence of a sensitive cyano functional group. The specific activity of these two radioligands was measured and [3H]6b found to be suitable for use in D4 saturation and competition binding studies. The synthesis, biological, and radioactivity of this new agonist radioligand as well as preliminary SAR will be discussed.