ABSTRACT
A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.
Subject(s)
Amides/chemistry , Amides/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Amides/chemical synthesis , Amides/metabolism , Animals , Cell Line , Glutathione/chemistry , Humans , Mice , Molecular Structure , Neurons/drug effects , Neurons/metabolism , Phenol/chemistry , Phenols/chemistry , Structure-Activity RelationshipABSTRACT
(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.
Subject(s)
N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/metabolism , Pain , Piperidines/chemistry , Quinolones/chemistry , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/metabolism , Inhibitory Concentration 50 , Molecular Structure , Pain/drug therapy , Piperidines/pharmacology , Quinolones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
Subject(s)
Drug Design , Ether-A-Go-Go Potassium Channels/metabolism , N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Administration, Oral , Inhibitory Concentration 50 , Molecular Structure , N-Methylaspartate/administration & dosage , Pyridines/chemical synthesis , Solubility , Structure-Activity RelationshipSubject(s)
Neoplasms, Fibrous Tissue/surgery , Spinal Cord Neoplasms/surgery , Antigens, CD34/analysis , Biomarkers, Tumor/analysis , Cell Division/physiology , Collagen/analysis , Humans , Laminectomy , Male , Middle Aged , Neoplasms, Fibrous Tissue/pathology , Spinal Cord/pathology , Spinal Cord/surgery , Spinal Cord Neoplasms/pathology , Thoracic Vertebrae/surgery , Vimentin/analysisABSTRACT
BACKGROUND: Our data in rats suggest that an elevated amniotic fluid erythropoietin (EPO) level at birth indicates antepartum fetal hypoxia. However, the short gestation period in rats does not permit a direct comparison of our data with humans. METHODS: We conducted a retrospective study of the relationship between EPO levels at birth and abnormal fetal heart rate (FHR) records in 113 infants. RESULTS: Among the cesarean section group, the cord serum and amniotic fluid EPO levels in the infants with antepartum abnormal FHR records were significantly higher than those in the control infants. Among the vaginal delivery group, the cord serum EPO levels in the infants with intrapartum abnormal FHR records was significantly higher than that in the control infants. The EPO levels in either cord serum and amniotic fluid discriminated between infants with antepartum abnormal FHR records. The control infants had a sensitivity of 83% and a specificity of 96%. Six of the seven infants with abnormal EPO levels in both cord serum and amniotic fluid had symptoms of prolonged fetal hypoxia. Five infants with abnormal EPO levels in only cord serum had symptoms of acute fetal hypoxia before birth. Four of the 14 infants with abnormal EPO levels at birth had poor outcomes in the neonatal period. CONCLUSIONS: We concluded that EPO levels in both cord serum and amniotic fluid at birth are valuable for determining the timing of fetal hypoxia and may predict the outcome in the neonatal period.
Subject(s)
Amniotic Fluid/chemistry , Erythropoietin/analysis , Fetal Blood/chemistry , Heart Rate, Fetal/physiology , Female , Fetal Hypoxia/diagnosis , Humans , Pregnancy , Retrospective Studies , Sensitivity and SpecificityABSTRACT
The experimental data of pi-facial stereoselection of the imines and the iminium ions of cyclohexanone, tropinone, and adamantan-2-ones have been explained by the exterior frontier orbital extension model (EFOE model) previously proposed. In all cases, facial difference in the pi-plane-divided accessible space (PDAS), which represents simple summation of the pi-plane-divided exterior three-dimensional space nearest to the reaction center outside the van der Waals surface, significantly depends on the structure of the imino moieties. In particular the formation of iminium salt significantly affects the magnitude of both the EFOE density and the PDAS values.
