RESUMO
Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Animais , Antipsicóticos/síntese química , Antipsicóticos/química , Antipsicóticos/farmacologia , Benzazepinas/química , Bioensaio , Modelos Animais de Doenças , Agonistas de Dopamina/química , Agonismo Parcial de Drogas , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, 8b and 21a, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay.
RESUMO
A series of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones were synthesized and found to have potent activity at the glycine site of the NMDA receptor. In some cases, these compounds possessed poor aqueous solubility that may have contributed to poor rat oral bioavailability. Subsequently, compounds have been identified with improved aqueous solubility and oral bioavailability. Several of these compounds were examined in a rat chronic constrictive injury (CCI) model of neuropathic pain and found to have potent activity when dosed orally.
Assuntos
Analgésicos/síntese química , Dor/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Piridazinas/síntese química , Quinolinas/síntese química , Receptores de Glicina/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Alcinos/síntese química , Alcinos/química , Alcinos/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Encéfalo/metabolismo , Doença Crônica , Constrição Patológica/complicações , Masculino , Dor/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Piridazinas/química , Piridazinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Nervo Isquiático/patologia , Relação Estrutura-AtividadeRESUMO
Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.
