RESUMO
The synthesis and structure-activity relationships of a series of aza-tricyclic analogs of the quinuclidine substance P (SP) antagonist 1 are described. The SP receptor affinity of these compounds was found to vary according to the size of the new ring fused to the quinuclidine and the mode of fusion. Correlations between receptor affinity and (1) the steric bulk of the newly introduced ring fusion and (2) the dihedral angle between the benzhydryl and benzylamino substituents of these aza-tricyclic compounds were explored.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Substância P/antagonistas & inibidores , Animais , Linhagem Celular , Cobaias , Humanos , Masculino , Quinuclidinas/síntese química , Quinuclidinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Relação Estrutura-Atividade , Ureter/efeitos dos fármacosRESUMO
(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994) binds selectively and with high affinity (Ki = 0.25 nM) to neurokinin (NK)-1 tachykinin receptors in a human cell line and in guinea pigs where it acts as an antagonist as evidenced by its blockade of substance P-induced excitation of locus coeruleus neurons in vitro. Subcutaneously administered CP-99,994 antagonized locomotor activity in guinea pigs induced by intraventricular infusion of [Sar9,Met(O2)11]-substance P (50 micrograms) with an ID50 = 0.59 mg/kg, indicating that CP-99,994 penetrates into the central nervous system. Orally administered CP-99,994 potently blocked (ID50 = 4 mg/kg) the leakage of Evans blue dye into trachea and bronchi elicited by exposure of guinea pigs to aerosol capsaicin (1 mM). CP-99,994 has reduced affinity (IC50 = 3 microM) for the L-type calcium channel in contrast to CP-96,345 (IC50 = 27 nM) an earlier nonpeptide antagonist. Thus, CP-99,994 represents an important pharmacological tool for investigating the physiological role of substance P and a potentially novel therapeutic agent for treating a variety of diseases.
Assuntos
Piperidinas/farmacologia , Receptores da Neurocinina-1/efeitos dos fármacos , Animais , Ligação Competitiva , Canais de Cálcio/metabolismo , Permeabilidade Capilar/efeitos dos fármacos , Capsaicina/farmacologia , Células Cultivadas , Cricetinae , Cobaias , Humanos , Técnicas In Vitro , Locus Cerúleo/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Piperidinas/metabolismo , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-2/efeitos dos fármacos , Receptores da Neurocinina-2/metabolismo , Receptores da Neurocinina-3/efeitos dos fármacos , Receptores da Neurocinina-3/metabolismo , Especificidade da Espécie , Substância P/metabolismoAssuntos
Neurocinina A/antagonistas & inibidores , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Albuterol/farmacologia , Animais , Ligação Competitiva , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/metabolismo , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Cinética , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Piperidinas/metabolismo , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-1/fisiologia , Tiorfano/farmacologia , Verapamil/análogos & derivados , Verapamil/metabolismoRESUMO
Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.
Assuntos
Analgésicos/farmacologia , Asma/fisiopatologia , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Dor/fisiopatologia , Receptores da Neurocinina-2/metabolismo , Substância P/metabolismo , Animais , Ligação Competitiva , Modelos Animais de Doenças , Inflamação , Receptores da Neurocinina-2/efeitos dos fármacosAssuntos
Quinuclidinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Animais , Humanos , Estrutura Molecular , Antagonistas dos Receptores de Neurocinina-1 , Quinuclidinas/química , Ratos , Receptores da Neurocinina-1/efeitos dos fármacos , Relação Estrutura-Atividade , Substância P/antagonistas & inibidoresRESUMO
We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.
Assuntos
Compostos de Bifenilo/farmacologia , Substância P/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Compostos de Bifenilo/química , Capsaicina/farmacologia , Células Cultivadas , Córtex Cerebral/metabolismo , Cricetinae , Extravasamento de Materiais Terapêuticos e Diagnósticos , Cobaias , Humanos , Masculino , Dados de Sequência Molecular , Ratos , Ratos Endogâmicos , Salivação/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl) methyl]-1-azabicyclo[2.2.2]octan-3-amine) antagonism of substance P-stimulated salivation was investigated in pentobarbital-anesthetized rats. Administered either intraperitoneally or orally, CP-96,345 produced dose-dependent inhibition of the sialogogic response elicited by substance P, with a median effective dose of 12-24 mumol/kg (5-10 mg/kg) of body weight, but had no effect on acetylcholine-stimulated salivation. CP-96,345 produced concentration-dependent inhibition of [3H]substance P binding to rat submaxillary gland membranes, with a median effective concentration of 34 +/- 3.6 nM. These biological activities were confined to CP-96,345 in that the 2R,3R enantiomer (CP-96,344) was without effect.
Assuntos
Compostos de Bifenilo/farmacologia , Glândula Parótida/fisiologia , Receptores de Neurotransmissores/fisiologia , Saliva/metabolismo , Glândula Submandibular/fisiologia , Substância P/farmacologia , Animais , Ligação Competitiva , Membrana Celular/metabolismo , Relação Dose-Resposta a Droga , Cinética , Masculino , Glândula Parótida/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores da Neurocinina-1 , Receptores de Neurotransmissores/antagonistas & inibidores , Receptores de Neurotransmissores/efeitos dos fármacos , Saliva/efeitos dos fármacos , Glândula Submandibular/efeitos dos fármacos , Substância P/metabolismoRESUMO
CP-96,345 [(2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)- methyl]-1-azabicyclo[2.2.2]octan-3-amine] is a potent nonpeptide antagonist of the substance P (NK1) receptor. CP-96,345 inhibited 3H-labeled substance P binding and was a classical competitive antagonist in the NK1 monoreceptor dog carotid artery preparation. CP-96,345 inhibited substance P-induced salivation in the rat, a classical in vivo bioassay, but did not inhibit NK2, NK3, or numerous other receptors; it is thus a selective NK1 antagonist. This compound may prove to be a powerful tool for investigation of the physiological properties of substance P and exploration of its role in diseases.
