ABSTRACT
Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. Tumor necrosis factor alpha (TNF-alpha) plays a central role as a pro-inflammatory cytokine in COPD. TNF-alpha release is markedly inhibited by phosphodiesterase type 4 (PDE4) inhibitors that have proven efficacious in COPD clinical trials. The aim of this study was to compare the in vitro activities of the novel selective PDE4 inhibitors CI-1044 compared to well-known PDE4 inhibitors, rolipram and cilomilast, and to the glucocorticoid dexamethasone at reducing lipopolysaccharide (LPS)-induced TNF-alpha release in whole blood from COPD patients and healthy subjects. In the whole blood from COPD patients pre-incubation with PDE4 inhibitors or dexamethasone resulted in a dose-dependent inhibition of LPS-induced TNF-alpha release with IC(50) values of 1.3+/-0.7, 2.8+/-0.9 microM, higher to 10 microM and lesser than 0.03 microM for CI-1044, rolipram, cilomilast and dexamethasone, respectively. We observed a similar inhibition in the whole blood from healthy volunteers with, however, higher IC(50) values. These results indicate that CI-1044 inhibits in vitro LPS-induced TNF-alpha release in whole blood from COPD patients better than rolipram and cilomilast and suggested that it could be a useful anti-inflammatory therapy in COPD.
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , 3',5'-Cyclic-AMP Phosphodiesterases/pharmacology , Azepines/pharmacology , Niacinamide/analogs & derivatives , Phosphodiesterase Inhibitors/pharmacology , Polysaccharides, Bacterial/pharmacology , Pulmonary Disease, Chronic Obstructive/blood , Tumor Necrosis Factor-alpha/antagonists & inhibitors , 3',5'-Cyclic-AMP Phosphodiesterases/therapeutic use , Adult , Azepines/therapeutic use , Carboxylic Acids/pharmacology , Carboxylic Acids/therapeutic use , Cyclic Nucleotide Phosphodiesterases, Type 4 , Cyclohexanecarboxylic Acids , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Dose-Response Relationship, Drug , Female , France , Humans , Male , Middle Aged , Niacinamide/pharmacology , Niacinamide/therapeutic use , Nitriles/pharmacology , Nitriles/therapeutic use , Phosphodiesterase Inhibitors/therapeutic use , Polysaccharides, Bacterial/drug effects , Pulmonary Disease, Chronic Obstructive/drug therapy , Rolipram/pharmacology , Rolipram/therapeutic use , Tumor Necrosis Factor-alpha/drug effects , Tumor Necrosis Factor-alpha/metabolismABSTRACT
A series of new 3-amino, 3-aminomethyl-5-alkoxy-3,4-dihydro-2H-1-benzopyran and 5'-alkoxy-3',4'-dihydrospiro-[piperazine-2.3'(2'H)-benzopyran] derivatives was prepared and evaluated for affinity at 5-HT1A, 5-HT2A and D2 receptors. Two of the compounds (1f and 2b) can be considered as potent and selective 5-HT2A ligands. One compound (1g) demonstrated high affinity for 5-HT1A and D2 receptor binding sites and one compound (1d) proved to be a mixed 5-HT1A/5-HT2A ligand.
Subject(s)
Amines/chemistry , Amines/metabolism , Benzopyrans/chemistry , Benzopyrans/metabolism , Amines/chemical synthesis , Benzopyrans/chemical synthesis , Binding Sites , Humans , Inhibitory Concentration 50 , Ligands , Receptor, Serotonin, 5-HT2A , Receptors, Dopamine D2/metabolism , Receptors, Serotonin/metabolism , Receptors, Serotonin, 5-HT1 , Structure-Activity RelationshipABSTRACT
In connection with the development of new potential 5-HT1A ligands, multistep synthesis of N-substituted-3-aminomethyl-2,3-dihydro-1,4-dioxinol[2,3-b]pyridin e derivatives as ORG13514 analogs are described. Their biological activity as 5-HT1A type ligands is reported and compared with ORG13514 affinity and selectivity for 5-HT1A receptors.
Subject(s)
Dioxins/chemistry , Receptors, Serotonin/metabolism , Serotonin Agents/chemical synthesis , Serotonin Agents/pharmacology , Spiro Compounds/chemical synthesis , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/metabolism , Dioxins/chemical synthesis , Dioxins/metabolism , Electroencephalography , Male , Radioligand Assay , Rats , Receptors, Serotonin, 5-HT1 , Serotonin Agents/metabolism , Sleep/physiology , Spectrum Analysis , Spiro Compounds/chemistry , Spiro Compounds/metabolism , Wakefulness/physiologyABSTRACT
In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.
