RESUMO
The synthesis, structure-activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
Assuntos
3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Antiasmáticos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Azepinas/síntese química , Indóis/síntese química , Niacinamida/síntese química , Inibidores de Fosfodiesterase/síntese química , 3',5'-GMP Cíclico Fosfodiesterases , Animais , Antiasmáticos/efeitos adversos , Antiasmáticos/química , Antiasmáticos/farmacologia , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Aorta/enzimologia , Azepinas/química , Azepinas/metabolismo , Azepinas/farmacologia , Ligação Competitiva , Encéfalo/metabolismo , Lavagem Broncoalveolar , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 1 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Eosinófilos/patologia , Furões , Cobaias , Humanos , Técnicas In Vitro , Indóis/efeitos adversos , Indóis/química , Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Masculino , Monócitos/enzimologia , Niacinamida/análogos & derivados , Niacinamida/química , Niacinamida/metabolismo , Niacinamida/farmacologia , Ovalbumina/imunologia , Fosfodiesterase I , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Ensaio Radioligante , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Traqueia/enzimologia , Fator de Necrose Tumoral alfa/biossíntese , Vômito/induzido quimicamenteRESUMO
This study compares the antinociceptive and orexigenic activities of NPY and analogs after intracerebroventricular administration in mice. NPY had an antinociceptive action in the mouse writhing test which was not affected by prior treatment with naltrexone, yohimbine, idazoxan or reserpine. A detailed examination revealed that NPY (0.023-0.7 nmol), PYY (0.007-0.07 nmol), NPY2-36 (0.023-0.23 nmol) and the Y1 agonist [Leu31, Pro34]-NPY (0.07-0.7 nmol) all produced a dose-dependent and complete suppression of acetic acid-induced writhing. In contrast, the Y2 agonist, NPY13-36, had little or no antinociceptive effect. As shown by their ED50 values, the relative potency of the peptides was PYY > NPY2-36 > or = NPY > [Leu31, Pro34]-NPY > > NPY13-36, suggesting that a Y1 rather than a Y2 or Y3 receptor subtype was implicated in the antinociceptive action. Thereafter, all peptides were assessed for their effects on food intake. With respect to dose and peptide specificity, the hyperphagic effects of NPY and related peptides paralleled those on nociception, suggesting a common receptor mechanism. However, a purported NPY antagonist, [D-Trp32]-NPY, attenuated NPY's effect on feeding yet this same peptide elicited a dose-dependent inhibition of acetic acid-induced writhing, suggesting some molecular distinction between antinociception and stimulation of food intake.