RESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/farmacología , Receptores de Neurotransmisores/antagonistas & inhibidores , Animales , Unión Competitiva , Compuestos de Bifenilo/química , Arterias Carótidas/efectos de los fármacos , Bovinos , Perros , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Conejos , Ratas , Receptores de Neuroquinina-1 , Salivación/efectos de los fármacos , Estereoisomerismo , Sustancia P/metabolismo , Sustancia P/farmacologíaRESUMEN
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.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/farmacología , Sustancia P/antagonistas & inhibidores , Animales , Línea Celular , Cobayas , Humanos , Masculino , Quinuclidinas/síntesis química , Quinuclidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Relación Estructura-Actividad , Uréter/efectos de los fármacosRESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/farmacología , Sustancia P/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Compuestos de Bifenilo/química , Capsaicina/farmacología , Células Cultivadas , Corteza Cerebral/metabolismo , Cricetinae , Extravasación de Materiales Terapéuticos y Diagnósticos , Cobayas , Humanos , Masculino , Datos de Secuencia Molecular , Ratas , Ratas Endogámicas , Salivación/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Analgésicos/farmacología , Asma/fisiopatología , Compuestos de Bifenilo/metabolismo , Compuestos de Bifenilo/farmacología , Dolor/fisiopatología , Receptores de Neuroquinina-2/metabolismo , Sustancia P/metabolismo , Animales , Unión Competitiva , Modelos Animales de Enfermedad , Inflamación , Receptores de Neuroquinina-2/efectos de los fármacosAsunto(s)
Neuroquinina A/antagonistas & inhibidores , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/farmacología , Albuterol/farmacología , Animales , Unión Competitiva , Canales de Calcio/efectos de los fármacos , Canales de Calcio/metabolismo , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Cobayas , Cinética , Pulmón/efectos de los fármacos , Pulmón/fisiología , Piperidinas/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-1/fisiología , Tiorfan/farmacología , Verapamilo/análogos & derivados , Verapamilo/metabolismoAsunto(s)
Quinuclidinas/farmacología , Receptores de Neuroquinina-1/metabolismo , Sustancia P/metabolismo , Animales , Humanos , Estructura Molecular , Antagonistas del Receptor de Neuroquinina-1 , Quinuclidinas/química , Ratas , Receptores de Neuroquinina-1/efectos de los fármacos , Relación Estructura-Actividad , Sustancia P/antagonistas & inhibidoresRESUMEN
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.
Asunto(s)
Compuestos de Bifenilo/farmacología , Glándula Parótida/fisiología , Receptores de Neurotransmisores/fisiología , Saliva/metabolismo , Glándula Submandibular/fisiología , Sustancia P/farmacología , Animales , Unión Competitiva , Membrana Celular/metabolismo , Relación Dosis-Respuesta a Droga , Cinética , Masculino , Glándula Parótida/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores de Neuroquinina-1 , Receptores de Neurotransmisores/antagonistas & inhibidores , Receptores de Neurotransmisores/efectos de los fármacos , Saliva/efectos de los fármacos , Glándula Submandibular/efectos de los fármacos , Sustancia P/metabolismoRESUMEN
(+)-(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.