ABSTRACT
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.
Subject(s)
Quinolines/pharmacology , Receptors, Serotonin, 5-HT1/drug effects , Administration, Oral , Animals , Biological Availability , Ligands , Quinolines/administration & dosage , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Chemistry, Pharmaceutical/methods , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Administration, Oral , Animals , Chromatography/methods , Drug Design , Humans , Kinetics , Male , Models, Chemical , Molecular Conformation , Rats , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
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.
Subject(s)
Insecticides/chemical synthesis , Limonins/chemical synthesis , Insecticides/chemistry , Limonins/chemistry , Molecular Conformation , StereoisomerismABSTRACT
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.
Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Blood-Brain Barrier/metabolism , Cerebral Cortex/metabolism , Humans , In Vitro Techniques , Piperazines/pharmacokinetics , Piperazines/pharmacology , Quinolines/pharmacokinetics , Quinolines/pharmacology , Radioligand Assay , Rats , Recombinant Proteins/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Receptors, Serotonin/metabolism , Serotonin Agents/metabolism , Administration, Oral , Biological Availability , Ligands , Serotonin Agents/pharmacokineticsABSTRACT
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.
Subject(s)
Benzoxazines/chemical synthesis , Benzoxazines/pharmacology , Receptor, Serotonin, 5-HT1A/drug effects , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacology , Animals , Binding, Competitive/drug effects , CHO Cells , Callithrix , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , Guinea Pigs , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Piperazines/pharmacology , Pyridines/pharmacology , Radioligand Assay , Rats , Receptor, Serotonin, 5-HT1B/drug effects , Receptor, Serotonin, 5-HT1D/drug effects , Synaptosomes/drug effectsABSTRACT
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.
Subject(s)
Imidazoles/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Cyclization , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Proto-Oncogene Proteins B-raf/chemistry , Structure-Activity RelationshipABSTRACT
[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.
Subject(s)
Ellipticines/chemical synthesis , Antineoplastic Agents/chemical synthesis , CarbazolesABSTRACT
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.
Subject(s)
Imidazolidines/administration & dosage , Imidazolidines/pharmacology , Serotonin 5-HT2 Receptor Antagonists , Administration, Oral , Animals , Cell Line , Humans , Imidazolidines/chemical synthesis , Imidazolidines/chemistry , Molecular Structure , Rats , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2B/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Sensitivity and Specificity , Structure-Activity Relationship , Substrate SpecificityABSTRACT
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.
