RESUMEN
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Asunto(s)
Quinolinas/farmacología , Receptores de Serotonina 5-HT1/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Ligandos , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Asunto(s)
Piperazinas/síntesis química , Quinolinas/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Barrera Hematoencefálica/metabolismo , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Piperazinas/farmacocinética , Piperazinas/farmacología , Quinolinas/farmacocinética , Quinolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Proteínas Recombinantes/farmacología , Relación Estructura-ActividadRESUMEN
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Asunto(s)
Insecticidas/síntesis química , Limoninas/síntesis química , Insecticidas/química , Limoninas/química , Conformación Molecular , EstereoisomerismoRESUMEN
Novel 2-methyl-5-quinolinyl-1-piperazinylalkyl-3,4-dihydro-2H-1,4-benzoxazin-3-ones showing high affinities for the 5-HT(1A/1B/1D) receptors coupled with potent 5-HT reuptake inhibitory activity have been discovered. This is the first report describing docking of the lead compound 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2H-1,4-benzoxazin-3(4H)-one 1, into a model of the 5-HT transporter and the 5-HT(1A) receptor model.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Administración Oral , Animales , Cromatografía/métodos , Diseño de Fármacos , Humanos , Cinética , Masculino , Modelos Químicos , Conformación Molecular , Ratas , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Asunto(s)
Receptores de Serotonina/metabolismo , Serotoninérgicos/metabolismo , Administración Oral , Disponibilidad Biológica , Ligandos , Serotoninérgicos/farmacocinéticaRESUMEN
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Asunto(s)
Benzoxazinas/síntesis química , Benzoxazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Callithrix , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Cobayas , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Piperazinas/farmacología , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Receptor de Serotonina 5-HT1D/efectos de los fármacos , Sinaptosomas/efectos de los fármacosRESUMEN
A novel triarylimidazole derivative, SB-590885 (33), bearing a 2,3-dihydro-1H-inden-1-one oxime substituent has been identified as a potent and extremely selective inhibitor of B-Raf kinase.
Asunto(s)
Imidazoles/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Ciclización , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Proteínas Proto-Oncogénicas B-raf/química , Relación Estructura-ActividadRESUMEN
[reaction: see text] Imidoyl selanides, synthesized from amides, have been used as radical precursors of imidoyl radicals in cascade reactions. The novel radical cascade has been developed for the simple synthesis of the medicinally important aryl-annulated[b]carbazoles. The protocol has been exemplified with the high-yielding total synthesis of the anticancer alkaloid ellipticine.
Asunto(s)
Elipticinas/síntesis química , Antineoplásicos/síntesis química , CarbazolesRESUMEN
Bisaryl cyclic ureas have been identified as high affinity 5-HT2C receptor antagonists with selectivity over 5-HT2A and 5-HT2B. Compounds such as 8 and 22 have shown oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function in rodents.
Asunto(s)
Imidazolidinas/administración & dosificación , Imidazolidinas/farmacología , Antagonistas del Receptor de Serotonina 5-HT2 , Administración Oral , Animales , Línea Celular , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/química , Estructura Molecular , Ratas , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Sensibilidad y Especificidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The synthesis of novel 3-(octahydropyrido[1,2-a]pyrazin-2-yl)- and 3-(hexahydropyrrolo[1,2-a]pyrazin-2-yl)phenyl-2-benzo[b]thiophene sulphonamide derivatives 3, (S)-4 and (R)-4 is described. The compounds show high affinity for the 5-HT6 receptor, excellent selectivity against a range of other receptors and good brain penetration.