Dass 3 metabolite

TABLE 1. Effect of repeated systemic administration of MDMA and MDA on NE, DA, and DA metabolite levels in various regions of rat brain ... 

Increase the levels of DA metabolites, such as homovanillic acia (HVA). 

In addition to acute and chronic schizophrenia, the neuroleptics are sometimes used in the management of mania, delirium, and severe agitation, whatever the cause of these symptom complexes. It must be noted that unlike parkinsonism, where a definite dysfunction in the DA system has been established, for schizophrenia and other psychiatric diseases, no unequivocal evidence has yet been presented to prove that there is a disturbance of the DA system (e.g., dopaminergic overactivity or receptor hypersensitivity). In untreated schizophrenics the production of DA metabolites is normal. Conflicting results have been obtained in studies of the DA receptors in schizophrenics (11,12,13), but in the case of patients who have not received neuroleptics, the receptor density and affinity appear to be normal (13). The "dopamine hypothesis" in these disorders derives from the beneficial effects of drugs that block DA receptors. 

DA or a toxic DA metabolite might contribute to the degeneration of both dopaminergic and serotonergic nerve terminals and,... 

Fig. 6 Enzyme cofactor screening. Binding of preferred substrate, poor substrate, and non-preferred adenine-nucleotide cofactors to the metabolic enzyme GDH. A NADP (765 Da, preferred substrate) binding shows a clear equilibrium concentration-response relationship. B NAD (663 Da, metabolite) shows a lower equilibrium binding level, and compressed concentration-response relationship. C FAD (830 Da, non-preferred substrate) shows very low levels of equilibrium binding...

An aspect of neuroleptic therapy that has been puzzling is the delay of three or more weeks before subjective improvement is noted, even though it can be shown that the drugs block D2 receptors at the beginning of therapy. It has been known for some time that schizophrenics have much higher levels of homovanillic acid (HVA), which is the major DA metabolite, than do healthy controls. The fact that HVA concentrations parallel alterations in DA turnover in the brain has also been understood. It was demonstrated that fluphenazine steadily decreased HVA levels after several weeks and can ultimately reach normal values. Moreover, in patients that were evaluated, improvement correlates well with the HVA levels. This delayed effectiveness, then, may indicate that decreased DA turnover is the important factor rather than the immediate DA receptor blockade. It should be realized that in humans antipsychotics may have increased HVA levels in the CSF over the first few weeks, apparently because of DA blockade, which likely increases DA synthesis as a compensatory mechanism in the presynaptic neuron. After that initial 3-week period, however, DA turnover decreases to normal levels while the drug is continuing. 

Several clinical studies have shown buspirone (14a) to have anxiolytic efficacy equivalent to that of DZ with significantly less sedation. ° Rats trained to discriminate oxazepam or pentobarbital from vehicle did not generalize to buspirone. At doses above those which are anxiolytically relevant in man, the drug caused a dose-related elevation of plasma prolactin in male subjects, and like the BZ s also increased growth hormone levels. Buspirone elicits a dose-dependent rise in rat striatal dopamine (DA) metabolite levels and may do so by selective antagonism of presynaptic DA autoreceptors with minimal postsynaptic effects. Its catalepsy-reversal effects may occur... 

If the low DA values were due to a particularly rapid breakdown of DA which was formed at normal rate then concentrations of HVA the main DA metabolite would be high. However, abnormally low HVA concentrations have been found in the caudate nucleus and putamen of patients with Parkinson s disease [105, 115] and therefore defective DA formation is indicated. The high HVA/DA ratio reported suggests that DA in surviving DA-ergic neurones is turned over abnormally rapidly. 

There have been many studies of urinary amine metabolites in Parkinson s disease. Early work (reviewed in ref. 151) showed low DA concentration and is contradicted by one recent study [152] but confirmed by another [153] in which excretion of free but not of conjugated DA by a group of subjects with parkinsonism of various origins was significantly lower than that of a control group on the same diet. Excretion of the DA metabolite 3,4-dihydroxyphenylacetic acid was also... 

With the LC-MS interfaces now available, a wide range of analytes, from low-molecular-weight drugs and metabolites (<1000 Da) to high-molecular-weight biopolymers (>100000 Da), may be studied. 

The MS-MS data from metabolite 5 shows a base peak at m/z 437, at an increase of 16 Da over the parent drug, but, in common with Indinavir, ions at m/z 364 and 465. Of most significance is the ion at m/z 465 which indicates that the extra oxygen atom is associated with the indan ring structure. 

The MS-MS spectrum of the (M + H)+ ion from the parent drug contains an ion at m/z 465, the structure of which is indicated in Figure 5.40. The mass spectrum of metabolite 1 indicates that it has a molecular weight of 482 Da, while the MS-MS spectrum from its MH+ ion contains both an ion at m/z 466 and aXm/z 364, also present in that from the MH+ of the parent drug. It is not unreasonable, although not necessarily always correct, to assume that the ion of... 

The electrospray mass spectrnm of metabolite 2 indicates it has a molecular weight of 522 Da, while the MS-MS spectrum of the (M + H)+ ion contains an intense ion at m/z 422, 1 Da greater than the base peak of the MS-MS spectrnm of the protonated molecnlar ion of the parent drug. If we assume a similar relationship between these ions as assnmed for m/z 465 and m/z 466 above, it is not nnreasonable to postnlate the strnctnre of metabolite 2 to be that shown in Fignre 5.44. 

There are many similarities between the MS-MS spectra of the (M + H)" " ions of metabolites 2 and 3, with the molecnlar weight of the latter being 16 Da greater than the former. Ions occnr in both spectra at m/z 374 and 273, thns snggesting that this additional oxygen atom has been incorporated into the indan-ring part of the molecnle. 

Table 5.14 Summary of the accurate mass differences (in Da) between the molecnlar ion of Glyburide and the molecular ions of five of its metabolites." Reprinted with permission from Zhang, H., Henion, J., Yang, Y. and Spooner, N., Anal. Chem., 72, 3342-3348 (2000). Copyright (2000) American Chemical Society...

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