cyclic-gmp and pyridine

Paroxysmal nocturnal hemoglobinuria (PNH) patients display exaggerated intravascular hemolysis and esophageal disorders. Since excess hemoglobin in the plasma causes reduced nitric oxide (NO) bioavailability and oxidative stress, we hypothesized that esophageal contraction may be impaired by intravascular hemolysis. This study aimed to analyze the alterations of the esophagus contractile mechanisms in a murine model of exaggerated intravascular hemolysis induced by phenylhydrazine (PHZ). For comparative purposes, sickle cell disease (SCD) mice were also studied, a less severe intravascular hemolysis model. Esophagus rings were dissected free and placed in organ baths. Plasma hemoglobin was higher in PHZ compared with SCD mice, as expected. The contractile responses produced by carbachol (CCh), KCl, and electrical-field stimulation (EFS) were superior in PHZ esophagi compared with control but remained unchanged in SCD mice. Preincubation with the NO-independent soluble guanylate cyclase stimulator 3-(4-amino-5-cyclopropylpyrimidin-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (BAY 41-2272; 1

Topics: Anemia, Sickle Cell; Animals; Cyclic GMP; Esophageal Diseases; Esophagus; Guanylate Cyclase; Hemolysis; Male; Mice; Mice, Inbred C57BL; Models, Animal; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase Type III; Nitroprusside; Oxidative Stress; Phenylhydrazines; Pyrazoles; Pyridines; Signal Transduction; Soluble Guanylyl Cyclase

Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]-pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines.

Topics: Binding Sites; Catalytic Domain; Cell Proliferation; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclization; HT29 Cells; Humans; Hydrolysis; Molecular Docking Simulation; Phosphodiesterase 3 Inhibitors; Protein Binding; Pyridines; Pyrimidines; Structure-Activity Relationship; Substrate Specificity

The bacterial signaling molecule, cyclic diguanosine monophosphate (c-di-GMP), plays a key role in controlling biofilm formation and pathogenic virulence, among many other functions. It has widespread consequences for human health, and current research is actively exploring its molecular mechanisms. The convenient one-flask, gram-scale synthesis of c-di-GMP described here will facilitate these efforts.

Topics: Bacteria; Chromatography, High Pressure Liquid; Crystallization; Cyclic GMP; Cyclization; Dichloroacetic Acid; Ethylamines; Pyridines; Solutions; Time Factors

The pharmacological and toxicological activity of pyridine was determined in rat thoracic aorta. Pyridine inhibited norepinephrine (3 microM)-induced phasic and tonic contractions in the thoracic aorta as well as the endothelium-denuded aorta of the rat. The tonic pre-contraction elicited by norepinephrine was also relaxed by the addition of pyridine and this relaxing effect was not affected by indomethacin (20 microM), NG-monomethyl-L-arginine acetate (50 microM) or methylene blue (50 microM). In high-K+ medium (80 mM), pyridine inhibited the Ca2+ concentration-dependent vasocontraction. Moreover, in Ca(2+)-free medium, the norepinephrine (3 microM)-induced phasic contraction was also suppressed by pyridine, while the caffeine (10 mM)-induced contraction remained unaffected. The cAMP and cGMP levels of rat aorta were not changed by pyridine. The 45Ca2+ influx elicited by either norepinephrine or high-K+ was inhibited by pyridine in a concentration-dependent manner. All of these findings indicated that pyridine relaxes rat thoracic aorta by virtue of its Ca2+ channel-blocking properties in vascular smooth muscle.

Topics: Animals; Aorta, Thoracic; Caffeine; Calcium; Cyclic AMP; Cyclic GMP; Endothelium, Vascular; Female; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Norepinephrine; Potassium; Pyridines; Rats; Rats, Wistar