Metabolite antagonism

The recognition of the quantitatively almost unmatched ability of p-aminoben-zoic acid (PABA) to oppose the bacteriostatic efficiency of the sulfonamides led Woods and Fildes [19, 20] to formulate the fundamentals of the theory of metabolite antagonism (Fig. 1.1). 

The antibacterial activity—and toxicity—of a sulfanilamide stems from a rather simple fact enzymes in the bacteria (and in the patients) confuse it for p-amino-benzoic acid, which is an essential metabolite. In what is known as metabolite antagonism the sulfanilamide competes with p-aminobenzoic acid for reactive... 

Baker, B. R. Metabolite antagonism by enzyme inhibition. In Medicinal chemistry, Vol. I. (ed. A. Burger). New York Wiley 1970. 

Table 9.1 Some van der Waals radii relevant to metabolite antagonism. Speakman, 1968.)...

The anticoagulant action of coumarins resembles the Symptoms observed in vitamin K deficiency [436], and clinical observations on the reversibility of the coumarin effect by adequate amounts of vitamin K also indicate a competition between these compounds. However, this concept may represent an over-simplification because no single enzyme system has been identified where such a metabolite—anti-metabolite antagonism takes place [437]. It has been suggested that vitamin K and the anticoagulant coumarins exert their action in the liver cell at different levels [438]. They may interact with the regulation of the synthesis of vitamin K-dependent factors [439,440]. 

Enzymes, their substrates and other metabolites. 289 Metabolite analogues definition, derivation, and mode of action. 295 History of metabolite antagonism prior to 1940. 302 The folic acid antagonists. 303... 

Studies of metabolite antagonism were foreshadowed by the London work of Ringer (1883) who found, from a helper s error which he was quick to interpret, that the sodium (cations) in a solution of sodium chloride could not maintain the beat of an isolated heart unless balanced by calcium and potassium. As a result of this work, the physiologically balanced solutions, named after Ringer, Locke, and Tyrode, were developed. 

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

The neurotoxic effects of all these compounds are antagonized by inhibitors of monoamine uptake (table 1), implicating the membrane uptake carrier on serotonin and dopamine neurons in the mechanism of neurotoxicity. In this regard, these amphetamines are like a drug somewhat related in structure, namely l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a Parkinsonism-causing neurotoxic dmg that has been studied intensely since 1983 (Langston and Irwin 1986). In the case of MPTP, the mechanism by which inhibitors of the dopamine uptake carrier block the neurotoxicity toward dopamine neurons (mainly nigrostriatal dopamine neurons) seems clear. A metabolite of MPTP, l-methyl-4-phenylpyridinium (MPP-I-), has been shown to be a substrate for the dopamine uptake carrier (Javitch et al. 1985). Thus accumulation of MPP-I-, formed metabolically from... 

GR 38032F had no significant effects on brain levels of DA or 5-HT or their oxidative metabolites in various brain regions in rats [111]. However, this compound selectively antagonized DA metabolism in rats with activated meso-limbic system. 

Chenoweth believes that an explanation of the above results may lie in the reactions occurring before the entrance of fatty acid metabolites into the citric acid cycle. Activated acetate, i.e. acetyl coenzyme A (AcCoA) is the end-product of fatty acid metabolism prior to its condensation with oxalacetate to form citrate. Possibly fluoro-fatty acids behave like non-fluorinated fatty acids. The end-product before the oxalacetate condensation could be the same for all three fluorinated inhibitors, viz. fluoroacetyl coenzyme A (FAcCoA). Fluorocitrate could then be formed by the condensation of oxalacetate with FAcCoA, thereby blocking the citric acid cycle. The specificity of antagonisms must therefore occur before entrance of the metabolites into the citric acid cycle. 

C. Sakurada, C. Watanabe, S. Sakurada, K. Tan-no, T. Sakurada, Major Metabolites of Substance P Degraded by Spinal Synaptic Membranes Antagonize the Behavioral Response to Substance Pin Rats , J. Pharm. Sci. 1999, 88, 1127-1132. 

These include trazodone and a derivative of its metabolite nefazodone, both of which are strongly sedative, an effect which has been attributed to their potent alpha-1 receptor antagonism rather than to any antihistaminic effects. A main advantage of these drugs in the treatment of depression is that they appear to improve the sleep profile of the depressed patient. Their antidepressant activity is associated with their weak 5-HT reuptake inhibition and also a weak alpha-2 antagonism. However, unlike most of the second-generation antidepressants, neither drug is effective in the treatment of severely depressed patients. Furthermore, there is some evidence that trazodone can cause arrythmias, and priapism, in elderly patients. 

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