RESUMEN
A series of novel, potent and selective pyrido[1,2-a]pyrazine dopamine D4 receptor antagonists are reported including CP-293,019 (D4 Ki = 3.4 nM, D2 Ki > 3,310 nM), which also inhibits apomorphine-induced hyperlocomotion in rats after oral dosing.
Asunto(s)
Antagonistas de Dopamina/síntesis química , Antagonistas de los Receptores de Dopamina D2 , Actividad Motora/efectos de los fármacos , Pirazinas/síntesis química , Pirimidinas/síntesis química , Animales , Apomorfina/farmacología , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Diseño de Fármacos , Haloperidol/farmacología , Indicadores y Reactivos , Estructura Molecular , Pirazinas/química , Pirazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Receptores de Dopamina D4 , Relación Estructura-ActividadRESUMEN
The syntheses of a centrally active nonpeptide CRF1 receptor antagonist 2, butylethyl[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine (CP-154,526), and its analogs 11-14 and [3H]-2 are reported. The in vitro CRF1 receptor binding affinity in the series 2, the pharmacokinetic properties of 2 in rats, and the anxiolytic-like effects of orally administered 2 are presented.
Asunto(s)
Pirimidinas/síntesis química , Pirroles/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiolíticos/farmacología , Miedo , Masculino , Estructura Molecular , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Ventrículos Cerebrales/fisiología , Hormona Liberadora de Corticotropina/farmacología , Locus Coeruleus/fisiología , Neuronas/fisiología , Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica , Adenilil Ciclasas/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Unión Competitiva , Callithrix , Línea Celular , Membrana Celular/enzimología , Corteza Cerebral/enzimología , Ventrículos Cerebrales/efectos de los fármacos , Hormona Liberadora de Corticotropina/administración & dosificación , Perros , Cobayas , Humanos , Inyecciones Intraventriculares , Cinética , Masculino , Neuronas/efectos de los fármacos , Hipófisis/enzimología , Pirimidinas/administración & dosificación , Pirimidinas/metabolismo , Pirroles/administración & dosificación , Pirroles/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidoresRESUMEN
The synthesis of a series of alkylcarbamates of 1,5-methano-2,3,4,5-tetrahydro-1H-2-benzazepin-7-ol is reported. Many of these compounds are potent acetylcholinesterase (AChE) inhibitors. The in vitro AChE inhibition, cholinergic effects, acute toxicity, and elevation of brain acetylcholine levels in vivo of this series of compounds are described. A representative compound, 1d (5.6 mg/kg, po), was able to reverse hemicolinium-3-induced amnesia in the mouse passive avoidance assay.
Asunto(s)
Benzazepinas/síntesis química , Carbamatos/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Administración Oral , Amnesia/tratamiento farmacológico , Animales , Reacción de Prevención/efectos de los fármacos , Benzazepinas/farmacología , Carbamatos/farmacología , Carbamatos/uso terapéutico , Inhibidores de la Colinesterasa/administración & dosificación , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Colinesterasas/metabolismo , Relación Dosis-Respuesta a Droga , Inyecciones Intraperitoneales , Espectroscopía de Resonancia Magnética , Masculino , RatonesRESUMEN
The synthesis of a series of 1,2,3,3a,8,8a-hexahydroindeno[2,1-b]pyrrole 5-alkylcarbamates and their resolution are reported. These compounds are structurally related to physostigmine with substitution of a methylene group in place of the NMe group at position 8 of physostigmine. Many of these 8-carbaphysostigmine analogues are more potent acetylcholinesterase inhibitors in vitro and less toxic in vivo than physostigmine. The (-)-enantiomer (e.g., 1d and 1g) possessing the same absolute configuration at C3a and C8a as that of physostigmine, is about 6 to 12-fold more potent at inhibiting acetylcholinesterase than the corresponding (+)-enantiomer (e.g., 1e and 1h).