RESUMEN
Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.
Asunto(s)
Canales Iónicos/metabolismo , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Pirrolidinas/farmacología , Receptores Colinérgicos/efectos de los fármacos , Calcio/metabolismo , Dopamina/metabolismo , Humanos , Activación del Canal Iónico/efectos de los fármacos , Canales Iónicos/efectos de los fármacos , Receptores Colinérgicos/química , Proteínas RecombinantesRESUMEN
REsin Activation/Capture APproach or REACAP Technology, a novel approach to the synthesis of compound libraries, capitalizes on the formation and retention of a resin-bound reactive intermediate, which can be subsequently transformed into a stable, covalently attached molecule. Any unreacted "reactive intermediate" is quenched and removed from the resin upon work-up, leaving only the desired product on the solid support. In contrast to more traditional solid-supported chemistry that must address issues such as resin-loading, capping of unreactive functionalized moieties, and reaction yields, REACAP offers an attractive alternative with the focus more on the purity of the released products and less on yield. In an endeavor to generate truly non-peptide leads, we describe herein the synthesis of N-acyl-2-substituted-dihydro-4-pyridones, dihydro-4-pyridones, 4-ketopiperidines, tetrahydropyridines, and 2-acyl-3,7,8-substituted-5-oxo-2-azabicyclo[2.2.2]octane and triaza analogs using REACAP Technology.
Asunto(s)
Compuestos de Piridinio/síntesis química , Resinas de Plantas , Bases de Datos como Asunto , Diseño de Fármacos , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Compuestos de Piridinio/químicaAsunto(s)
Neuronas/metabolismo , Agonistas Nicotínicos/síntesis química , Nootrópicos/síntesis química , Fenoles/síntesis química , Pirrolidinas/síntesis química , Receptores Nicotínicos/metabolismo , Animales , Unión Competitiva , Línea Celular , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Agonistas Nicotínicos/metabolismo , Agonistas Nicotínicos/farmacología , Nootrópicos/metabolismo , Nootrópicos/farmacología , Oocitos , Técnicas de Placa-Clamp , Fenoles/metabolismo , Fenoles/farmacología , Pirrolidinas/metabolismo , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Transfección , XenopusRESUMEN
A series of conformationally restricted analogues of nicotine has been synthesized and evaluated as agonists of neuronal acetylcholine receptors. Compound 2 (SIB-1663), which selectively activated human recombinant alpha 2 beta 4 and alpha 4 beta 4 nAChRs, was shown to be active in animal models of Parkinson's disease and pain.
Asunto(s)
Anabasina/análogos & derivados , Anabasina/química , Agonistas Colinérgicos/síntesis química , Neuronas/metabolismo , Nicotina/análogos & derivados , Nicotina/química , Piperidinas/síntesis química , Piridinas/síntesis química , Anabasina/síntesis química , Anabasina/farmacología , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/química , Antiparkinsonianos/farmacología , Calcio/metabolismo , Línea Celular , Agonistas Colinérgicos/química , Agonistas Colinérgicos/farmacología , Diseño de Fármacos , Humanos , Sustancias Macromoleculares , Conformación Molecular , Nicotina/síntesis química , Nicotina/farmacología , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Piperidinas/química , Piperidinas/farmacología , Piridinas/química , Piridinas/farmacología , Proteínas Recombinantes/efectos de los fármacos , Relación Estructura-Actividad , TransfecciónRESUMEN
Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-alpha-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (-)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 microM, respectively. Such stimulation was sensitive to mecamylamine and DH beta E. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1765F was less efficacious than (-)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (-)-nicotine. Similar to (-)-nicotine and (+/-)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (-)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for h alpha 4 beta 2 NAChR relative to h alpha 4 beta 4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic CA+2 concentration in cell lines stably expressing h alpha 4 beta 2 or h alpha 4 beta 4.
Asunto(s)
Canales Iónicos/agonistas , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Pirrolidinas/farmacología , Animales , Calcio/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Masculino , Microdiálisis , Norepinefrina/metabolismo , Vías Olfatorias/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismoAsunto(s)
Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacología , Neuronas/fisiología , Piridinas/síntesis química , Piridinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores Nicotínicos/fisiología , Animales , Antiparkinsonianos/química , Línea Celular , Femenino , Humanos , Cinética , Estructura Molecular , Oocitos/fisiología , Técnicas de Placa-Clamp , Piridinas/química , Pirrolidinas/química , Receptores Nicotínicos/efectos de los fármacos , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Estereoisomerismo , XenopusRESUMEN
Steroidal antiestrogens appear to have at least two major modes of action in breast cancer cells, direct antagonism of estrogen binding to its receptor and depletion of estrogen receptors (ER) due to inhibition of dimerization of the receptor and a resultant destabilization of the receptor protein. In a search for other classes of compounds which would act as dimerization inhibitors, a novel substituted indole (8-{2-[1-(4-chlorobenzoyl)-5-hydroxy-2-methyl-1H-indol-3-yl]-acetylamino} octanoic acid butyl-methyl amide, MDL 101,906) was synthesized. Binding of the ER to its consensus response element (ERE) was apparently decreased in nuclear extracts from MCF-7 human breast cancer cell treated with MDL 101,906. This decreased binding was found to be due to depletion of ER based on direct measurement of ER using an enzyme-linked immunoassay. Other transcription factors were apparently unaffected by MDL 101,906 treatment. Whereas depletion of ER with a steroidal antiestrogen was almost complete after 3 h of treatment of MCF-7 cells, the effect of MDL 101,906 took significantly longer to occur, suggesting a fundamental difference in the mechanisms of action of the two drugs. This was also evident in the lack of binding of MDL 101,906 to the hormone binding domain of ER. MDL 101,906 treatment also caused depletion of ER mRNA in MCF-7 cells. Depletion of ER mRNA was noted by 3 h of drug treatment and was apparently almost complete after 24 h of treatment. Depletion of ER from MCF-7 cells led to a dose-dependent decrease in the expression of luciferase by an ERE-driven luciferase reporter gene assay system. The mechanism of MDL 101,906 appears to be unique and additional studies with this chemical class seem to be warranted to assess the potential for therapeutic utility.
Asunto(s)
Neoplasias de la Mama/química , Antagonistas de Estrógenos/farmacología , Indoles/farmacología , Receptores de Estrógenos/análisis , Secuencia de Bases , Unión Competitiva , Neoplasias de la Mama/metabolismo , Extractos Celulares , Núcleo Celular , ADN/metabolismo , Relación Dosis-Respuesta a Droga , Estradiol/análogos & derivados , Estradiol/metabolismo , Estradiol/farmacología , Antagonistas de Estrógenos/síntesis química , Expresión Génica , Genes Reporteros/genética , Humanos , Indoles/síntesis química , Datos de Secuencia Molecular , Alcamidas Poliinsaturadas , ARN Mensajero/análisis , ARN Neoplásico/análisis , Receptores de Estradiol/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Factores de Tiempo , Factores de Transcripción/metabolismo , Células Tumorales CultivadasAsunto(s)
Glicina/antagonistas & inhibidores , Quinurenina/análogos & derivados , Quinurenina/metabolismo , Liasas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Estricnina/farmacología , Transaminasas/metabolismo , Animales , Sitios de Unión , Unión Competitiva , Corteza Cerebral/enzimología , Cromatografía Líquida de Alta Presión , Ciclización , Glicina/metabolismo , Cinética , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Based on mechanistic understandings, molecular modeling and extensive quantitative structure-activity relationships, appropriately substituted haloallylamine derivatives were designed as potential mechanism-based inhibitors of MAO and/or SSAO. Potent inhibition of MAO-B and SSAO occurred with fluoroallylamines whereas chloroallylamines, such as MDL 72274A ((E)-2-phenyl-3-chloroallylamine hydrochloride), were selective and potent inhibitors of SSAO. MDL 72974A (E)-2-(4-fluorophenethyl)-3-fluoroallylamine hydrochloride is a potent (IC50 = 10(-9) M) inhibitor of both MAO-B and SSAO, with 190-fold lower affinity for MAO-A. In clinical studies, oral doses as low as 100 micrograms produced substantial inhibition of platelet MAO-B. Essentially complete inhibition occurred at 1 mg with the effect lasting 6-10 days. One or 4 mg MDL 72974A given daily for 28 days to 40 Parkinson's patients treated with L-dopa produced statistically significant reductions in the Unified Parkinson's Disease Rating Scale. MAO-B inhibitors, such as MDL 72974A and L-deprenyl, offer the potential of being neuroprotective in Parkinson's Disease and other neurogenerative disorders. Concommitant inhibition of SSAO may provide additional, but as yet unproven, advantages over pure inhibitors of MAO-B.
Asunto(s)
Compuestos Alílicos/uso terapéutico , Amina Oxidasa (conteniendo Cobre) , Butilaminas/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/antagonistas & inhibidores , Enfermedad de Parkinson/tratamiento farmacológico , Propilaminas/uso terapéutico , Semicarbacidas/farmacología , Animales , Evaluación de Medicamentos , Humanos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
MDL 72,974A [(E)-2-(4-fluorophenethyl)-3-fluoroallylamine, hydrochloride] was designed to be a selective, mechanism-based irreversible inhibitor of monoamine oxidase type B (MAO-B). The compound is a potent, selective MAO-B inhibitor in vitro and in vivo. In vitro studies revealed an IC50 value (MAO-B) of 3.6 nM with 189-fold selectivity compared to MAO-A. In rats, profound inhibition of MAO-B was achieved after a single oral dose with an ED50 of 0.18 mg/kg; a dose 44 times this amount was required to inhibit MAO-A by 50%. Selectivity was maintained following chronic dosing. MDL 72,974A had minimal sympathomimetic effects and did not potentiate the cardiovascular effects of tyramine, even at 50 times the MAO-B inhibiting dose. This inhibitor was equally effective and well-tolerated in man. In human volunteers, potent inhibition of platelet MAO-B activity was observed at submilligram doses (ED50 = 90 micrograms) following a single oral dose. Upon multiple oral doses of 100 micrograms, as much as 80% of MAO-B could be inhibited. In phase II studies, MDL 72,974A is proving to be a useful adjunct to conventional therapy. Patients (250) with Parkinson's disease, treated once daily with either 1 or 4 mg, together with L-Dopa and a decarboxylase inhibitor (MadoparR or SinemetR), saw significant improvements in symptoms compared with those on standard therapy without the inhibitor.
Asunto(s)
Compuestos Alílicos , Antiparkinsonianos/uso terapéutico , Butilaminas/farmacocinética , Butilaminas/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Monoaminooxidasa/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antiparkinsonianos/farmacocinética , Plaquetas/enzimología , Encéfalo/enzimología , Butilaminas/farmacología , Perros , Masculino , Inhibidores de la Monoaminooxidasa/farmacocinéticaRESUMEN
The N-methyl-D-aspartate (NMDA)-preferring glutamate receptor subtype possesses, in addition to the recognition site for glutamate, a binding site for glycine. We report here on the pharmacological properties of 3-(4,6-dichloro-2-carboxyindol-3-yl)-propionic acid (MDL 29,951) and 4-carboxymethylamino-5,7-dichloroquinoline-2-carboxylic acid (MDL 100,748), two novel glycine antagonists of NMDA receptor activation in vitro and in vivo. We have measured in parallel the effects of two previously described glycine antagonists, 7-chlorokynurenic acid and 5,7-dichlorokynurenic acid. All were potent inhibitors of [3H]glycine binding. Ki values (microM) were 0.36 (7-chlorokynurenic acid), 0.08 (5,7-dichlorokynurenic acid), 0.07 (MDL 100,748) and 0.14 (MDL 29,951). MDL 100,748 and MDL 29,951 were approximately 2000-fold selective for the glycine binding site relative to the glutamate recognition sites. All four compounds completely inhibited the use-dependent binding of [3H]N-[1-(2-thienyl) cyclohexyl]-piperidine and were noncompetitive, glycine-reversible inhibitors of both NMDA-induced biochemical and electrophysiological responses in brain slice preparations. A competitive interaction with the glycine binding site was also evident in that MDL 29,951 and MDL 100,748 produced parallel rightward shifts in the glycine requirement for demonstration of NMDA-stimulated elevations in cytosolic calcium in cultured neuronal preparations. The glycine antagonists were potent anticonvulsants after their i.c.v. administration to audiogenic seizure-susceptible DBA/2J mice. Because the compounds chosen encompass a variety of chemical structures, the results indicate that glycine is required for NMDA receptor activation and that bioavailable glycine antagonists may form the basis of a novel therapy for epilepsy.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Glicina/antagonistas & inhibidores , Indoles/uso terapéutico , Propionatos/uso terapéutico , Quinolinas/uso terapéutico , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Estimulación Acústica , Animales , Sitios de Unión/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Calcio/metabolismo , Glicina/metabolismo , Indoles/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Propionatos/metabolismo , Quinolinas/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/prevención & control , Estricnina/metabolismoRESUMEN
A pharmacophore for the phosphono amino acid antagonists of the NMDA receptor has been developed using computer-based molecular modeling techniques. An important feature of this model is that a single binding site is proposed for the phosphonic acid moiety. All competitive antagonists we have examined incorporating amino acid and phosphonate groups in their structure fit the pharmacophore in energetically accessible conformations.
Asunto(s)
Organofosfonatos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Unión Competitiva , Simulación por Computador , Electricidad , Modelos MolecularesRESUMEN
A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor. Chlorine, and other small electron-withdrawing substituents in the 4- and 6-positions of the indole ring, greatly enhanced binding and selectivity for the glycine site over the glutamate site of the NMDA receptor; one of the most potent compounds is 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (IC50 = 170 nM; greater than 2100-fold selective for glycine). The importance of a heteroatom NH and the enhancing effect of the propionic acid side chain were demonstrated and are consistent with previous results which suggest the presence of a pocket on the receptor which can accept an acidic side chain. Substitution of a sulfur at C3 led to the most potent compound 3-[(carboxymethyl)thio]-2-carboxy-4,6-dichloroindole (IC50 = 100 nM).
Asunto(s)
Glicina/metabolismo , Indoles/farmacología , Propionatos/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Sitios de Unión , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Ratones , Ratones Endogámicos DBA , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Convulsiones/prevención & control , Relación Estructura-Actividad , Estricnina/farmacología , Especificidad por SustratoRESUMEN
We have assessed the capacity of two novel inhibitors to block cytokine-induced nitric oxide (NO) synthesis by macrophages and vascular smooth muscle cells, as well as NO production by the constitutive enzyme in central nervous system tissue. NG-Cyclopropyl-L-arginine selectively inhibited Ca2+/calmodulin-dependent NO synthesis, with an IC50 of 0.55 microM in brain versus 184 and 258 microM in macrophages and vascular smooth muscle cells, respectively. In contrast, NG-amino-L-homoarginine blocked NO production by all of the cell types examined, with IC50 values ranging from 6.6 to 26 microM. Both inhibitors were active in an in vivo model of endotoxic shock.
Asunto(s)
Arginina/análogos & derivados , Cerebelo/efectos de los fármacos , Homoarginina/análogos & derivados , Macrófagos/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico/metabolismo , Animales , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Cerebelo/metabolismo , Homoarginina/farmacología , Macrófagos/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Ratas , Ratas Endogámicas , Choque Séptico/fisiopatologíaRESUMEN
Inhibition of nitric oxide production by arginine analogues was examined in three cell systems; macrophages, CNS tissue and endothelial cells. Nitric oxide production was assessed indirectly using in vitro assays measuring nitrite production (macrophages), cGMP elevation (CNS) and acetylcholine-induced relaxation of aortic ring segments (endothelium). NG-monomethyl-L-arginine and NG-amino-L-arginine possessed similar inhibitory activity in all three assays, while NG-nitro-L-arginine displayed a striking selectivity for inhibition of brain and endothelial cell nitric oxide synthesis, with IC50 values of 0.05 microM in the CNS versus 200 microM in macrophages. These results suggest that distinct enzymes are responsible for nitric oxide synthesis in different cell types, and indicate that it may be possible to selectively modulate nitric oxide production in vivo.