RESUMEN
[reaction: see text] The first multicomponent domino transformation between 1,3-dicarbonyls 1, alpha,beta-unsaturated compounds 2, and functionalized amines 3 is described, providing a one-pot access to fused polyheterocyclic or spiropolyheterocyclic compounds 5 or 6 bearing an aminal function by formation of up to three new cycles, five novel bonds, and up to six stereogenic centers.
Asunto(s)
Aminas/química , Aminas/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Cetonas/química , Cetonas/síntesis química , Acroleína/química , Catálisis , Ciclización , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Piperidonas/síntesis química , Piperidonas/química , Estereoisomerismo , Relación Estructura-Actividad , Agua/químicaAsunto(s)
Analgésicos/farmacología , Indoles/farmacología , Inflamación/fisiopatología , Receptores de Neuroquinina-2/metabolismo , Sustancia P/antagonistas & inhibidores , Taquicininas/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Inflamación/tratamiento farmacológico , Isoindoles , Receptores de Neuroquinina-2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of new indole derivatives (2-28) has been prepared in the search for novel 5-HT uptake inhibitors. These compounds were obtained by the condensation of N-(chloroalkyl) naphthalenesultam derivatives with the appropriate amine in presence of a base, at reflux of DMF or THF. The yields were moderate (12-56%), except for the piperazine derivative 20 (85%). The affinity of the compounds for uptake site and 5-HT2, alpha 1, and D2 receptors was measured. Some compounds were studied in vivo by their potentiating effect of 5-HTP-induced symptomatology. The most potent and selective (uptake, 5-HT2 versus alpha 1, D2 sites) compounds contain a 3-[(4-piperidinyl)methyl]indole moiety. 5-Fluoro-3-[(4-piperidinyl)methyl]indole itself (compound 1) displayed a high affinity for the uptake site but was devoided of in vivo activity. N-Methylation of this compound abolished the affinity. In contrast N-substitution by a two-carbon chain linked to a naphthalenesultam or related heterocycle led to compounds exhibiting high affinity for the uptake site. One of them, 1-[2-[4-((5-fluoro-1H-indol-3-yl)methyl-1- piperidinyl]ethyl]-5,6-dihydro-1H,4H-1,2,5-thiadiazolo[4,3,2- ij]quinoline 2,2-dioxide (compound 24), was found as active as fluoxetine in vivo.
Asunto(s)
Indoles/química , Indoles/síntesis química , Indoles/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Tiadiazoles/síntesis química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Fluoxetina/metabolismo , Fluoxetina/farmacología , Indoles/metabolismo , Masculino , Metilación , Estructura Molecular , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Tiadiazoles/metabolismo , Tiadiazoles/farmacologíaRESUMEN
The pharmacological properties of 7,7-Diphenyl-2 [1-imino-2 (2-methoxy-phenyl)-ethyl] perhydroisoindol-4-one (3 aR, 7 aR) or RP67580 are described. This compound, derived from a novel chemical family, is a potent and selective substance P (SP) antagonist, in vitro and in vivo. In vitro, it inhibited in a competitive manner (IC50 = 10 nM) 3H-SP binding in rat brain (NK1 receptors). It did not interact with the two other tachykinin receptor sites (NK2 and NK3) nor the other receptor sites tested. Moreover, RP67580 competitively antagonized the contractile activity of SP on guinea-pig ileum (pA2 = 7.16); in contrast, it was inactive in rabbit pulmonary artery and in rat portal vein tissues which contain NK2 and NK3 receptors, respectively. In vivo, in the rat, RP67580 inhibited the plasmatic extravasation induced by administration of SP (ED50 = 0.04 mg/kg i.v.) as well as that induced by antidromic stimulation of a peripheral sensory nerve (ED50 = 0.15 mg/kg i.v.). In mice and rats, RP67580, like morphine, potently blocked the nociceptive effects of phenylbenzoquinone and formalin; its antinociceptive effect does not involve opiate receptors since it was not reversed by naloxone. These results indicate that RP67580 is a particularly valuable tool for investigating the physiological and pathological role of SP.
Asunto(s)
Indoles/farmacología , Sustancia P/antagonistas & inhibidores , Analgésicos/administración & dosificación , Animales , Unión Competitiva/efectos de los fármacos , Interacciones Farmacológicas , Femenino , Cobayas , Técnicas In Vitro , Isoindoles , Masculino , Conejos , Ratas , Ratas Endogámicas , Receptores de Superficie Celular/metabolismo , Sustancia P/metabolismo , Taquicininas/metabolismoRESUMEN
We describe here the pharmacological properties of RP 67580 [(3aR,7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] perhydroisoindol-4-one], a nonpeptide antagonist of substance P (SP). In vitro, the compound was found to inhibit in a competitive manner (Ki = 4.16 +/- 0.59 nM) [3H]SP binding to neurokinin receptors type 1 (NK1 receptors) in rat brain membranes. Contractions induced by SP and septide (a selective NK1 agonist) in guinea pig ileum were competitively inhibited by RP 67580 (pA2 = 7.16 and 7.59, respectively). Moreover, RP 67580 displayed the profile of a specific antagonist of NK1 receptors: it was not active on NK2 and NK3 receptors as seen in binding assays and in isolated preparations of rabbit pulmonary artery and rat portal vein. In the rat, low intravenous doses of RP 67580 totally inhibited the plasma extravasation induced by SP in the urinary bladder (ED50 = 0.04 mg/kg i.v.) and by antidromic electrical stimulation of the saphenous nerve in the hind paw skin (ED50 = 0.15 mg/kg i.v.). This compound was also active in two classical analgesic tests in mice: phenylbenzoquinone-induced writhing (ED50 = 0.07 mg/kg s.c.) and the formalin test (ED50 = 3.7 mg/kg s.c.). Its potency was of the same order as that of morphine. Thus we conclude that RP 67580, a SP antagonist, belongs to a class of drugs that may be useful in the management of various clinical pathologies where pain and neurogenic inflammation are involved.
Asunto(s)
Analgésicos/farmacología , Íleon/fisiología , Indoles/farmacología , Músculo Liso Vascular/fisiología , Músculo Liso/fisiología , Vena Porta/fisiología , Receptores de Neurotransmisores/metabolismo , Sustancia P/antagonistas & inhibidores , Sustancia P/farmacología , Vejiga Urinaria/fisiología , Animales , Benzoquinonas/antagonistas & inhibidores , Benzoquinonas/toxicidad , Unión Competitiva , Femenino , Cobayas , Íleon/efectos de los fármacos , Técnicas In Vitro , Isoindoles , Cinética , Masculino , Ratones , Estructura Molecular , Morfina/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculos/efectos de los fármacos , Músculos/inervación , Músculos/fisiología , Vena Porta/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores de Neuroquinina-1 , Receptores de Neurotransmisores/efectos de los fármacos , Estereoisomerismo , Sustancia P/metabolismo , Vejiga Urinaria/efectos de los fármacosRESUMEN
A series of 2-(aminoalkyl)naphth[1,8-cd]isothiazole 1,1-dioxides was synthesized and examined in various receptor binding tests. Most compounds demonstrated high affinity for the 5-HT2 receptor with moderate to high selectivity. A member of this series, compound 24 (RP 62203), displays high 5-HT2 receptor affinity (Ki = 0.26 nM), which is respectively more than 100 and 1000 times higher than its affinity for alpha 1 (Ki = 38 nM) and D2 (Ki greater than 1000 nM) receptors. This compound is a potent orally effective and long lasting 5-HT2 antagonist in the mescaline-induced head-twitches test in mice and rats.