ABSTRACT
A series of new indolylalkylamides 3-18 and alkylamines 19-26 has been prepared in the search of novel 5-hydroxytryptamine (5-HT) uptake inhibitors. Synthesis of N-2,3 or 4-pyridinyl-(indol-3-yl) acetamides and propionamides 3-10 was achieved starting from the corresponding Ph3P/BrCCl3 or DCC-activated acids. Reduction of the pyridine nucleus led to the N-piperidinylalkylamides 15-18 via the tetrahydropyridinyl derivatives 11-14, and LiAlH4 reduction afforded the desired amines 19-26. The affinity of these compounds for 5-HT and also dopamine (DA) and noradrenaline (NA) uptake sites was measured. Among the 16 studied amides only N-(methylpiperidin-3-yl)-(indol-3-yl) propionamide 16 exhibited a moderate 5-HT uptake inhibitory effect: 38% at 10 mu mol/l. In contrast the N-pyridinyl-(indol-3-yl)alkylamines 19-26 exerted high inhibition at this concentration and two of them, 23 and 24, remained very efficient at 0.1 mu mol/l. Optimal activity was observed in the 4-pyridinyl subseries and was compatible with variation (n = 1, 2) of the length of the interspacing alkylamino chain. Although 23 and 24 were about 17-fold less active than indalpine as 5-HT uptake inhibitors, they demonstrated, like indalpine, excellent selectivity for the 5-HT uptake site versus the DA uptake site. Both amines inhibited tetrabenazine-induced hypothermia and potentiated 5-HTP-induced behavioural effects in mice. The absence of 3,4-dioxyphenylalanine (dopa)-induced behavioural effects with compound 24 suggests possible antidepressant activity through selective inhibition of central neuronal serotonin uptake and/or increased monoamine release.
Subject(s)
Antidepressive Agents/chemical synthesis , Indoles/chemical synthesis , Pyridines/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Animals , Antidepressive Agents/metabolism , Antidepressive Agents/pharmacology , Antidepressive Agents/toxicity , Blepharoptosis/chemically induced , Body Temperature/drug effects , Brain/drug effects , Brain/metabolism , Brain/ultrastructure , In Vitro Techniques , Indoles/metabolism , Indoles/pharmacology , Magnetic Resonance Spectroscopy , Male , Mice , Motor Activity/drug effects , Pyridines/metabolism , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Adrenergic/metabolism , Receptors, Dopamine/metabolism , Receptors, Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/toxicity , Synaptosomes/drug effects , Synaptosomes/metabolismABSTRACT
A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.
Subject(s)
Anti-Allergic Agents/chemical synthesis , Indoleacetic Acids/chemical synthesis , Pyridines/chemical synthesis , Acetylcholine/immunology , Animals , Anti-Allergic Agents/chemistry , Anti-Allergic Agents/pharmacology , Bronchoalveolar Lavage , Capillary Permeability/drug effects , Carbachol/pharmacology , Eosinophilia/immunology , Guinea Pigs , Histamine Release/drug effects , Hypersensitivity/immunology , In Vitro Techniques , Indoleacetic Acids/chemistry , Indoleacetic Acids/pharmacology , Interleukin-4/antagonists & inhibitors , Interleukin-5/antagonists & inhibitors , Male , Mast Cells/metabolism , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Peritoneal Cavity/cytology , Polyunsaturated Alkamides , Pyridines/chemistry , Pyridines/pharmacology , Rats , Rats, Sprague-Dawley , Rats, Wistar , Rhinitis, Allergic, Perennial/immunology , Rhinitis, Allergic, Perennial/prevention & control , Structure-Activity Relationship , Trachea/drug effects , Trachea/immunology , Trachea/physiologyABSTRACT
Troglitazone was obtained in 5 steps from 4-bromo-1,1-dimethoxy-3-methylbut-2-ene with an overall yield of 7.5%. The formation of the chromane ring was achieved by condensing an unsaturated acetal with trimethylhydroquinone in the presence of bis(trifluoromethylsulfonyl)imide.
