RESUMO
CP-96,345, a nonpeptide substance P antagonist, is selective for the tachykinin NK1 receptor. The compound binds to a single population of sites in guinea pig brain and potently inhibits substance P-induced excitation of locus ceruleus neurons. CP-96,345 should be a useful tool for studying the action of substance P in the central nervous system.
Assuntos
Compostos de Bifenilo/metabolismo , Encéfalo/metabolismo , Corpo Estriado/metabolismo , Receptores de Neurotransmissores/antagonistas & inibidores , Receptores de Neurotransmissores/metabolismo , Potenciais de Ação , Animais , Autorradiografia , Sítios de Ligação , Ligação Competitiva , Compostos de Bifenilo/farmacologia , Encéfalo/diagnóstico por imagem , Corpo Estriado/diagnóstico por imagem , Cobaias , Concentração de Íons de Hidrogênio , Masculino , Cintilografia , Receptores da Neurocinina-1 , Receptores de Taquicininas , Espectrofotometria , Substância P/metabolismo , Taquicininas/metabolismoRESUMO
A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.
Assuntos
Benzazepinas/farmacologia , Receptores da Colecistocinina/antagonistas & inibidores , Animais , Cristalografia por Raios X , Ácido Gástrico/metabolismo , Cobaias , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Pentagastrina/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B , Relação Estrutura-AtividadeRESUMO
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
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
A structurally novel series of cholecystokinin-B (CCK-B) receptor ligands has been designed and synthesized based on the 'double ring system' theory of receptor recognition. Compounds 2b-cis and 2g-cis from this 1-amino-2-benzyltetralin series show modest CCK-B receptor affinity, with IC50 values of 48.5 nM and 39.0 nM, respectively. The results are discussed in the context of ongoing efforts to identify the CCK-B receptor binding site for nonpeptide ligands.
Assuntos
Receptores da Colecistocinina/metabolismo , Sítios de Ligação , Fenômenos Químicos , Físico-Química , Desenho de Fármacos , Modelos Moleculares , Conformação Proteica , Receptor de Colecistocinina B , Receptores da Colecistocinina/químicaRESUMO
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
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
3-Amino-3-phenylpropionamide derivatives were produced as small molecule mimics of the cyclic octapeptide octreotide from readily available imine 1. The compounds exhibit high affinity for the mu opioid receptor.
Assuntos
Benzilaminas/síntese química , Receptores Opioides mu/efeitos dos fármacos , Animais , Benzilaminas/farmacologia , Química Encefálica , Células CHO , Cricetinae , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Ligantes , Octreotida/análogos & derivados , Octreotida/farmacologia , RatosRESUMO
The synthesis and SAR of benzylamine side chain analogs of the NK-1 receptor antagonist CP-99,994 are described. The 5-trifluoromethoxy analog, CP-122,721, shows superior in vivo blockade of NK-1 receptor mediated responses.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Animais , Capsaicina/antagonistas & inibidores , Linhagem Celular , Cobaias , Humanos , Atividade Motora/efeitos dos fármacos , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
(+)-(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/metabolismoRESUMO
CP-122,721 [(+)-(2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2 -phenylpiperidine] interacts with high affinity (pIC50 = 9.8) at the human NK1 receptor expressed in IM-9 cells. In the presence of CP-122,721, there was a reduction in Bmax of [125I]BH-SP binding with no change in affinity suggesting that CP-122,721 does not interact with the NK1 receptor in competitive manner. In an in vitro functional assay. CP-122,721 blocked SP-induced excitation of locus ceruleus cells in guinea pig brain slices with a IC50 value of 7 nM. In vivo, CP-122,721 potently blocked plasma extravasation in guinea pig lung elicited by aerosolized capsaicin (1 mM) with an ID50 = 0.01 mg/kg, p.o. Orally administered CP-122,721 antagonized Sar9, Met (O2)11-SP-induced locomotor activity in guinea pigs with an ID50 = 0.2 mg/kg suggesting good entry into the central nervous system. In addition, consistent with insurmountable blockade observed in vitro, CP-122,721 (0.01, 0.03 0.3 mg/kg, p.o.) produced a rightward shift in the dose response curve for SP-induced hypotension in the awake dog that was accompanied by a decrease in the maximal response. Thus, in vitro and in vivo CP-122,721 appears to behave functionally as a non-competitive antagonist producing an insurmountable blockade of the actions of SP.