RESUMO
In search of a uroselective alpha1A subtype selective antagonist, a novel series of 6-OMe hexahydrobenz[e]isoindoles attached to a bicyclic heterocyclic moiety via a two-carbon linker was synthesized. It was found that in contrast to the previously described series of tricyclic heterocycles,(1) this bicyclic series has very specific requirements for the heterocyclic attachments. The most important structural features contributing to the alpha1A/alpha1B selectivity of these compounds were identified. In vitro functional assays for the alpha1 adrenoceptor subtypes were used to further characterize the most selective compounds, and in vivo models of vascular vs prostatic tone were used to assess uroselectivity. Compound 48 showed the highest degree of selectivity in the radioligand binding assays (56-fold), in the in vitro functional tests (80-fold), and for in vivo prostate selectivity (960-fold).
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntese química , Indóis/síntese química , Prazosina/análogos & derivados , Hiperplasia Prostática/tratamento farmacológico , Quinazolinas/síntese química , Antagonistas Adrenérgicos alfa/química , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Linhagem Celular , Cães , Doxazossina/farmacologia , Desenho de Fármacos , Humanos , Indicadores e Reagentes , Indóis/química , Indóis/farmacologia , Isoindóis , Células L , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Prazosina/farmacologia , Próstata/metabolismo , Quinazolinas/química , Quinazolinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Adrenérgicos alfa 1 , Proteínas Recombinantes/antagonistas & inibidores , Baço/metabolismo , Relação Estrutura-Atividade , Ducto Deferente/metabolismoRESUMO
Analogs of compound 1 with a variety of azacycles and heteroaryl groups were synthesized. These analogs exhibited Ki values ranging from 0.15 to > 10,000 nM when tested in vitro for cholinergic channel receptor binding activity (displacement of [3H](-) cytisine from whole rat brain synaptic membranes).
Assuntos
Agonistas Colinérgicos/farmacologia , Animais , Encéfalo/metabolismo , Agonistas Colinérgicos/química , Agonistas Colinérgicos/metabolismo , Éteres/química , Ratos , Relação Estrutura-AtividadeAssuntos
Antagonistas de Receptores Adrenérgicos alfa 1 , Antagonistas Adrenérgicos alfa/síntese química , Indóis/síntese química , Hiperplasia Prostática/tratamento farmacológico , Pirimidinonas/síntese química , Antagonistas Adrenérgicos alfa/uso terapêutico , Animais , Cães , Humanos , Indóis/uso terapêutico , Isoindóis , Masculino , Modelos Químicos , Prazosina/análogos & derivados , Prazosina/uso terapêutico , Pirimidinonas/uso terapêutico , Ratos , Receptores Adrenérgicos alfa 1 , Sulfonamidas/uso terapêutico , TansulosinaRESUMO
Ligands which activate neuronal nicotinic acetylcholine receptors (nAChRs) represent a potential approach for the palliative treatment for the symptoms of memory loss associated with Alzheimer's disease (AD). Based upon this approach, a series of novel 3,5-disubstituted isoxazoles and isothiazoles were prepared and evaluated in vitro as cholinergic channel activators (ChCAs) of neuronal nAChRs. Many of the 3-substituted 5-(2-pyrrolidinyl)isoxazoles were found to have nanomolar binding affinities comparable to (S)-nicotine (2a) in a preparation of whole rat brain. However, in a paradigm measuring the evoked release of [3H]dopamine from a preparation of rat striatum, there were differences in the agonist potencies and efficacies of these analogues relative to 2a. The differences in agonist potency observed between compounds of comparable binding potency may be due to differences in ligand interactions with various subtypes of neuronal nAChRs.