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Biomedical subjects

M Schwarz

Publications and source records attributed to M Schwarz.

At least 145 records · Page 8Linked to original sources
PubMed1999

Characterization of human Kv4.2 mediating a rapidly-inactivating transient voltage-sensitive K+ current.

A human cDNA for the voltage-sensitive potassium channel subunit Kv4.2 has been cloned and functionally characterized. The human Kv4.2 (KCND2) gene was mapped at 7q31-32. Kv4.2 mRNA is prominently expressed in human brain. Relatively high concentrations of Kv4.2 mRNA occurred in mRNA preparations of amygdala, caudate nucleus, cerebellum, hippocampus, substantia nigra, and thalamus. Kv4.2 mRNA was not detected in human heart, kidney, liver, lung, pancreas, and skeletal muscle. The derived Kv4.2 open reading frame consists of 630 amino acids. In comparison to rat Kv4.2, the human Kv4.2 sequence is highly conserved showing amino acid sequence differences at five positions only. The Kv4.2 subunits were expressed heterologously in human embryonic kidney (293) cells and mediated a rapidly inactivating, A-type outward K+ current. The gating kinetics of the Kv4.2-mediated currents were very similar to those of rat Kv4.2-mediated currents. Both the Kv4.2 and Kv4.3 subunits have been implicated in mediating the transient outward K+ current Ito in rodent cardiac myocytes. In contrast we did not detect Kv4.2. but solely Kv4.3 mRNA in human heart RNA preparations. This may suggest that Kv4.2 subunits do not contribute to the rapid transient outward K+ current of atrial and ventricular myocytes in humans.

Amino Acid Sequence↗
PubMed1999

[Perioperative infection prophylaxis in gastrointestinal surgery].

Antibiotic perioperative prophylaxis is known to reduce postoperative infections and is generally administered as single-dose regimen today. Effective prophylaxis requires plasma- and tissue concentrations above the MIC of the expected bacterial spectrum throughout the whole operation from skin incision to wound closure. In longlasting operations a second dose after 4 hours is recommended. Indications for antibiotic prophylaxis are clean-contaminated or contaminated procedures according to Cruse and in patients with elevated risk of infection. Generally antibiotic prophylaxis is administered intravenously. Chinolons achieving high tissue- and plasmalevels and showing a broad antibacterial spectrum seem appropriate to be used for oral prophylaxis. In a prospective study in 36 patients pharmocokinetics of ofloxacin were measured perioperatively and proper plasma- and tissue concentrations were attained. A following prospective randomized study in 56 patients undergoing colonic or pancreatic resections oral prophylaxis did not show a higher infection rate compared with a standard intravenous prophylaxis. Therefore oral prophylaxis seems to be an attractive option, its effectivity needs to be proven by studies with sufficiently high patient numbers.

Anti-Bacterial Agents↗
PubMed1999

Prevalence of antibodies to West Nile fever, sandfly fever Sicilian, and sandfly fever Naples viruses in healthy adults in Israel.

BACKGROUND: The arbovirus infections West Nile fever (WNF) and sandfly fever (SFF) are both endemic in the Middle East. Despite the fact that the mosquito and sandfly vectors of these viruses are still found in Israel, SFF has not been reported since 1948, whereas outbreaks of WNF occur periodically. It is suspected that some of the cases of nonspecific febrile illnesses in Israel may in fact be either WNF or SFF. AIM: To determine the extent of past arbovirus infections in subgroups of Israeli soldiers. METHODS: Sera from random samples of three groups of healthy soldiers aged 18-20 (n=273), 21-30 (n=497), and 40-55 years (n=285) were examined for IgG and IgM antibodies to West Nile virus (WNV), sandfly fever Sicilian virus (SFSV), and sandfly fever Naples virus (SFNV), using an ELISA method. RESULTS: The prevalence of antibodies increased with age for all three viruses examined, and ranged from 7.0%, 0, and 2.8%, for WNV, SFSV, AND SFNV, respectively, in soldiers aged 18-20 years, to 41.9%, 23.7%, and 30.8%, in those aged 40-55 years. The percentage of seropositives for IgG who were also IgM positive were 1.0%, 5.9%, and 3.4%, for WNV, SFSV, AND SFNV, respectively. 17.5% of the seropositives for WNV were also positive for SFSV, as compared with 5.7% among the WNV-seronegatives. Among the seropositives for WNV, 23.99% were positive for SFNV, compared with 9.1% of WNV seronegatives. 48.2% of seropositives for SFSV were positive for SFNV, as compared with 8.4% for SFSV-seronegatives. In the age agroup 40-55 years, there were significantly higher prevalence rates in those born in Israel compared with those born abroad. CONCLUSIONS: There is still significant exposure to WNV, SFSV, and SFNV in Israel. Arborviruses are probably responsible for many cases of non-specific febrile illness in this region.

Adolescent↗
PubMed1998

Functional analysis of the human cytochrome P4501A1 (CYP1A1) gene enhancer.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) induces gene transcription, a process that requires binding of the activated aryl hydrocarbon receptor (AhR) to dioxin-responsive elements (DREs) within the enhancer region of responsive genes. Most of what is known about the molecular mechanism of AhR-dependent gene activation results from studies on the murine prototype TCDD-responsive gene cytochrome P4501A1 (CYP1A1). Much less is known, however, about the regulation of human TCDD-responsive genes. We have therefore conducted a detailed analysis of the enhancer region of the human CYP1A1 gene. From the ten DRE core motifs investigated within a stretch of 1400 bp in two human tumor cell lines using a ligation-mediated PCR technique, five motifs displayed a TCDD-inducible in vivo footprint. Four of these sites were functional enhancer sequences as demonstrated by a transient expression assay. Based on these data, a distinct functional consensus sequence for DRE motifs within the human CYP1A1 gene is suggested. After introduction of the four functional sites into various mouse hepatoma cell lines, only three exhibited a functional response, suggesting some species differences in CYP1A1 gene regulation. In addition to the footprints at DRE sites, we also detected protein-DNA interactions at three G-rich domains located within the enhancer region of the human CYP1A1 gene. Our data show that, besides some similarities in the regulation of the human and mouse CYP1A1 genes, there also exist some distinct differences, including number, location, and functional consensus sequences of DRE motifs, as well as quantity and location of footprinted G-rich domains.

Animals↗
PubMed1998

Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7alpha-hydroxylase gene causes severe neonatal liver disease.

We describe a metabolic defect in bile acid synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.

Amino Acid Sequence↗
PubMed1998

Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors.

The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a promising new antiplatelet strategy. The binding of ligands or of the ligand-mimetic peptide RGD causes a conformational change of GP IIb/IIIa from the nonactivated to the activated state. Because several blocking agents/inhibitors are ligand-mimetics, the current study evaluates whether these agents have the intrinsic property to activate GP IIb/IIIa. Fibrinogen binding to GP IIb/IIIa on platelets or on CHO cells expressing recombinant GP IIb/IIIa was evaluated by flow cytometry or 125I-labeled fibrinogen. Incubation with the monoclonal antibody (MoAb) fragment c7E3 (abciximab) results in fibrinogen binding to GP IIb/IIIa and in the access of ligand-induced binding sites. At low concentrations (0.01 to 0.1 microgram/mL), this intrinsic activating property of c7E3 can result in platelet aggregation. The disintegrin flavorodin and the RGD analogue fradafiban also induce fibrinogen binding, whereas the blocking MoAbs 2G12 and P2 and the activation-specific MoAb PAC-1 do not. Aspirin and indomethacin cannot block c7E3-induced fibrinogen binding to GP IIb/IIIa, but can inhibit c7E3-induced platelet aggregation. Thus, we conclude that GP IIb/IIIa inhibitors can demonstrate an intrinsic activating property, which can result in fibrinogen binding to GP IIb/IIIa and consequently in platelet aggregation. Cyclooxygenase inhibitors can inhibit platelet aggregation caused by GP IIb/IIIa inhibitors. Further studies will have to evaluate the clinical relevance of the potential intrinsic activating property of GP IIb/IIIa inhibitors and define consequences for the future drug development and evaluation of these potent antiplatelet agents.

Abciximab↗
PubMed1998

Mutations of the cystic fibrosis gene in patients with chronic pancreatitis.

BACKGROUND: The pancreatic lesions of cystic fibrosis develop in utero and closely resemble those of chronic pancreatitis. Therefore, we hypothesized that mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more common than expected among patients with chronic pancreatitis. METHODS: We studied 134 consecutive patients with chronic pancreatitis (alcohol-related disease in 71, hyperparathyroidism in 2, hypertriglyceridemia in 1, and idiopathic disease in 60). We examined DNA for 22 mutations of the CFTR gene that together account for 95 percent of all mutations in patients with cystic fibrosis in the northwest of England. We also determined the length of the noncoding sequence of thymidines in intron 8, since the shorter the sequence, the lower the proportion of normal CFTR messenger RNA. RESULTS: The 94 male and 40 female patients ranged in age from 16 to 86 years. None had a mutation on both copies of the CFTR gene. Eighteen patients (13.4 percent), including 12 without alcoholism, had a CFTR mutation on one chromosome, as compared with a frequency of 5.3 percent among 600 local unrelated partners of persons with a family history of cystic fibrosis (P<0.001). A total of 10.4 percent of the patients had the 5T allele in intron 8 (14 of 134), which is twice the expected frequency (P=0.008). Four patients were heterozygous for both a CFTR mutation and the 5T allele. Patients with a CFTR mutation were younger than those with no mutations (P=0.03). None had the combination of sinopulmonary disease, high sweat electrolyte concentrations, and low nasal potential-difference values that are diagnostic of cystic fibrosis. CONCLUSIONS: Mutations of the CFTR gene and the 5T genotype are associated with chronic pancreatitis.

Adolescent↗
PubMed1998

Expression of interleukin 6 in the rat striatum following stereotaxic injection of quinolinic acid.

Stereotaxic intrastriatal injection of the naturally occurring N-methyl-D-aspartate (NMDA) agonist quinolinic acid (QA) serves as a valuable in vivo model to study excitotoxic cell damage in the central nervous system (CNS). Although morphological changes such as neuronal loss, glial activation and remote reactions following QA injection have been described in some detail, much less is known about the molecular mechanisms mediating the accompanying glial response. Cytokines are known to play a crucial role in almost all kinds of CNS alterations. We now demonstrate that IL-6, a multifunctional glycoprotein which belongs to the family of neurokines, is expressed endogenously in the rat striatum following QA injection. Using Northern blot analysis, a massive but transient upregulation of IL-6 mRNA could be detected. This started 3 h after QA injection, reached a maximum at 6 h and disappeared within 24 h. That activated microglia are the most likely cellular source of the observed corresponding IL-6 protein expression could be concluded by comparing the immunocytochemical pattern of IL-6 expression and microglial activation. Interestingly, astrocytes initially downregulate their expression of glial fibrillary acidic protein (GFAP) in the excitotoxically injured striatum, but show a delayed increase in GFAP immunoreactivity starting in the periphery of the striatum, subsequently expanding to the core. The early transient IL-6 expression may play an important role in initiating the delayed astrocytic response following excitotoxic cell injury.

Animals↗
PubMed1998

Abscisic acid maintains S-type anion channel activity in ATP-depleted Vicia faba guard cells.

The plant hormone abscisic acid (ABA) regulates important developmental and stress responses. Recent data show that ABA activates phosphorylation events, but whether dephosphorylation events are post-translationally regulated by ABA or whether these are constitutive remains unknown. Slow anion channels in the plasma membrane of guard cells have been proposed to play an important role during ABA-induced stomatal closing. Anion channels are deactivated by removal of cytosolic ATP. However, when guard cells were treated with ABA and depleted of ATP, anion currents remained active. Subsequent removal of extracellular ABA caused deactivation of currents. Deactivation of currents was reversed by reintroduction of cytosolic MgATP. These data show that anion channels are regulated by ABA even in the absence of cytosolic ATP required for kinase-induced phosphorylation events and that anion channel activity is maintained by ABA under conditions that favor dephosphorylation-induced deactivation. Furthermore, channel activation proceeded at high ATP concentrations with nanomolar cytosolic Ca2+ showing a Ca2+-independent final step in anion channel activation.

Abscisic Acid↗
PubMed1998

Monitoring of multiple myeloma patients by simultaneously measuring marker substances of bone resorption and formation.

Fifteen patients (13 males and two females; mean age, 63 years; age range, 46-84 years) with multiple myeloma were studied prospectively (range of follow-up period, 2-6 months) to elucidate the diagnostic validity of biochemical markers of bone formation (bone alkaline phosphatase and the C-terminal propeptide of type I procollagen) and bone resorption (urinary excretion of pyridinium cross-links) for monitoring these patients. Eleven of 15 patients received melphalan i.v. and prednisone p.o. every 4 weeks. All patients were given pamidronate i.v. for inhibition of bone resorption. The mean values of the urinary excretion of pyridinium cross-links were significantly higher in the patients fulfilling the criteria of 'progression' or 'relapse' than in those showing 'response' and those in the 'plateau phase' (P < 0.05). In contrast, neither bone alkaline phosphatase nor C-terminal propeptide serum values differed significantly between these two groups (P > 0.05). The concentrations of both bone formation markers were significantly lower in the patients than in the samples obtained from apparently healthy persons (P < 0.001). There was a significant inverse correlation between the number of pamidronate courses and the serum concentrations of bone alkaline phosphatase (P < 0.05). A lack of correlation was observed between the urinary excretion of pyridinium cross-links and all other laboratory parameters measured (serum concentrations of total protein, calcium, creatinine and (beta 2-microglobulin). In conclusion, the urinary excretion of pyridinium cross-links might be a useful parameter for monitoring multiple myeloma patients. Decreased values of bone formation markers may be due to a suppressive effect of the bisphosphonate agents administered or reflect the severity of osteolytic lesions which have been described as being associated with unbalanced bone remodelling.

Aged↗
PubMed1998

IFN-gamma induces the high-affinity Fc receptor I for IgG (CD64) on human glomerular mesangial cells.

The deposition of immune complexes, followed by activation of complement and/or Fc receptors and generation of chemoattractants, is the most common feature of human glomerulonephritis. Recently we have shown that primary cultured human glomerular mesangial cells (HMC), which are normally negative for IgG Fc receptors, can be stimulated to express the low-affinity FcgammaRIII-A receptor isoform. In this study we further demonstrate that activation of HMC through IFN-gamma resulted in the functional expression of the high-affinity Fc receptor for IgG (FcgammaRI, CD64). IFN-gamma-dependent induction of classical FcgammaRIa1 mRNA as well as a2, b2 splice variants were evident after 24 h in proliferating HMC and after 48 h in resting HMC. Transcription of FcgammaRI mRNA was also induced by IL-10 in proliferating HMC, whereas other cytokines such as IL-3, transforming growth factor-beta1 and granulocyte-macrophage colony-stimulating factor were not effective. Cell surface expression of FcgammaRI could be detected by flow cytometric analysis after IFN-gamma stimulation and was accompanied by the augmentation of MHC class II and the up-regulation of intercellular adhesion molecule-1 expression. Triggering of HMC by cross-linking FcgammaRI with F(ab')2 fragments of the anti-CD64 monoclonal antibody 22 led to enhanced synthesis of mRNA for the chemokines IL-8 and monocyte chemoattractant protein-1, indicating that the FcgammaRI of HMC is functionally active. These in vitro data suggest that engagement of both FcgammaRI and FcgammaRIII-A on activated HMC through IgG immune complexes may result in an increased chemoattraction of leukocytes into the glomerulus, contributing to the development of glomerulonephritis.

Cells, Cultured↗
PubMed1998

p21Ras downstream effectors are increased in activity or expression in mouse liver tumors but do not differ between ras-mutated and ras-wild-type lesions.

Mouse liver tumors frequently harbor activating ras gene mutations. Downstream effector molecules of p21Ras include Raf-1 kinase which mediates external signals via kinase signaling pathways to nuclear transcription factors including c-Fos and c-Jun. Mouse liver tumors with differing ras-mutational status were analyzed for alterations in Ras/Raf-1 signal transduction. Tumors were characterized with respect to the presence of base substitutions in the 3 known hot-spot positions at codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras. Ha-ras codon 61 or Ki-ras codon 13 mutations, but no N-ras mutations, were detected in 23 out of 33 tumors analyzed, while no ras-mutations were found in 10 of the tumors. There was no significant difference in the expression of p21RaS proteins between ras-mutated tumors and tumors without detectable ras mutations. To allow for determination of Raf-1 kinase activity in tumors, a sensitive and specific assay was developed for measurements with tissue homogenates. Raf-1 kinase activity was increased about four-fold in liver tumors as compared with normal liver tissue. No significant differences in kinase activity, however, were evident between ras-mutated and ras-wild-type tumors. The same was true with respect to the levels of c-fos and c-jun mRNAs. Moreover, there were no significant differences in cell division (5-bromo-2'-deoxyuridine-labeling indices) of hepatocytes from ras-mutated and ras-wild-type tumors. The similar degree of constitutive activation of the Ras/Raf-1 signaling pathway in liver tumors, with and without detectable ras mutations, suggests that other molecules within the signaling pathway may substitute for ras-mutations during oncogenic conversion of ras-wild-type hepatocytes.

Animals↗
PubMed1998

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets.

These studies were undertaken to determine whether in young adult outbred CD-1 mice there were any gender-related differences in basal bile acid metabolism that might be important in determining how males and females in this species responded to a dietary cholesterol challenge. When fed a plain cereal-based rodent diet without added cholesterol, 3-month-old females, compared with age-matched males, manifested a significantly larger bile acid pool (89.1 vs. 54.1 micromol/100 g body weight), a higher rate of fecal bile acid excretion (13.6 vs. 8.5 micromol/d/100 g body weight), a more efficient level of intestinal cholesterol absorption (41.1% vs. 25. 3%), and a lower rate of hepatic sterol synthesis (338 vs. 847 nmol/h/g). Similar results were found in C57BL/6 and 129Sv inbred mice. In matching groups of CD-1 mice fed a diet containing 1% cholesterol for 21 days, hepatic cholesterol levels increased much more in the females (from 2.4 to 9.1 mg/g) than in the males (from 2. 1 to 5.2 mg/g). This occurred even though the level of stimulation of cholesterol 7-hydroxylase activity in the females (79%) exceeded that in the males (55%), as did the magnitude of the increase in fecal bile acid excretion (females: 262% vs. males: 218%). However, in both sexes, bile acid pool size expanded only modestly and by a comparable degree (females: 19% vs. males: 26%) so that in the cholesterol-fed groups, the pool remained substantially larger in the females than in the males (102.3 vs. 67.6 micromol/100 g body weight). Together, these data demonstrate that while male and female CD-1 mice do not differ qualitatively in the way cholesterol feeding changes their bile acid metabolism, the inherently larger bile acid pool in the female likely facilitates the delivery of significantly more dietary cholesterol to the liver than is the case in males, thereby resulting in higher steady-state hepatic cholesterol levels.

Animal Feed↗
PubMed1998

Neurophysiological abnormalities in the Westphal variant of Huntington's disease.

The Westphal variant of Huntington's disease (HD) is a distinct clinical entity of HD characterized by a rigid-hypokinetic syndrome and is often associated with a juvenile onset of disease. Definite genetic differences between the subtypes of HD have not been delineated so far. Here we present the results of a battery of neurophysiological tests including somatosensory-evoked potentials, blink reflexes, long-latency reflexes, and measurement of saccadic velocities in a Westphal HD patient. Although quantitative assessment of his motor performance showed a severe hypokinetic syndrome resembling Parkinson's disease, the results of somatosensory-evoked potentials and blink reflexes were indistinguishable from results obtained in hyperkinetic HD patients. Long-latency reflexes, however, which are typically absent in hyper-kinetic HD patients, were retained in this patient. It is concluded that neurophysiology in HD patients is not a mere reflection of the patient's symptomatology but can give insight into the underlying pathophysiological process.

Adult↗
PubMed1998

Expression of hypoxia-inducible genes in tumor cells.

Tumor tissue oxygenation impacts on proliferation of cancer cells and their sensitivity towards radio- and chemotherapy. Under low oxygen, mammalian cells show an adaptive response that leads to the induction of a number of genes with well-defined roles in oxygen supply and energy maintenance, e.g. genes encoding enzymes of the glycolytic pathway. The hypoxia-inducible factor 1 (HIF-1), a transcription factor consisting of the two proteins HIF-1alpha and HIF-1beta, plays a major role in the pleiotropic response observed under low oxygen. We have determined, by Northern analysis, the mRNA levels of HIF-1alpha and of two glycolytic enzymes known to be transcriptionally activated by HIF-1, namely phosphoglycerate kinase 1 (PGK 1) and pyruvate kinase M2 (PKM2), in different hepatoma cell lines and in mouse and human tissues. Hypoxic treatment of various mouse and human hepatoma cell lines led to the expected increase in the amount of PGK1 and PKM2 mRNA, while HIF-1alpha mRNA levels were not significantly elevated. Analysis of mouse liver tumors demonstrated no tumor-specific increases in HIF-1alpha or PGK1 mRNA levels. In five of eight human colorectal cancers investigated, PGK1 and PKM2 mRNA levels were increased in comparison to the corresponding normal tissues, while HIF-1alpha mRNA levels were not significantly changed. The majority of the colorectal cancers demonstrated p53 immunoreactivity, presumably due to mutation of the gene; there was, however, no correlation between the p53 staining pattern and mRNA expression levels of glycolytic enzymes.

Animals↗
PubMed1998

Flupirtine, a nonopioid centrally acting analgesic, acts as an NMDA antagonist.

1. Flupirtine (Katadolon) is a member of a class of triaminopyridines and is used as a nonopioid analgesic agent with muscle relaxant properties. 2. In situ experiments have revealed that flupirtine protects against ischemic-induced insults to the retina and brain. 3. Data derived from in vitro and in vivo studies suggest that flupirtine functions as a weak N-methyl-D-aspartate (NMDA) antagonist with little evidence that it acts on AMPA-kainate type glutamate receptors. 4. No evidence could be found from binding studies to suggest that flupirtine has an affinity for any of the characterized binding sites associated with the NMDA receptor. 5. Studies on cultured cortical neurons show that the NMDA-induced influx of 45Ca2+ is more readily decreased by flupirtine when a reducing agent (dithiothreitol) is present. However, when N'-ethylmaleimide, which is thought to alkylate the NMDA receptor redox site, is present, no obvious effect on the NMDA-induced influx of 45Ca2+ is produced by flupirtine. 6. Flupirtine is also known to counteract the production of reactive oxygen species caused by ascorbate/iron as well as to prevent apoptosis in cells lacking NMDA receptors induced by oxidative stress. 7. To explain all the experimental data, it is suggested that flupirtine affects the redox state/pH/electrons in the cell. The specific way by which flupirtine antagonizes the NMDA receptor might be by an action on the known redox site of the receptor.

Aminopyridines↗