- Synthesis and oxidant properties of phase 1 benzepine N-oxides of common antipsychotic drugs
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There is increasing evidence that cell constituents are oxidized by widely used antipsychotic drugs but until now the underlying chemistry has remained unclear. It is well known that such drugs readily undergo N-oxidation as a first key metabolic step. To gain insight into the problem, the tertiary phase 1 N-oxides of clozapine, olanzapine, quetiapine, and zotepine were synthesized, together with the N,S-dioxides of quetiapine and zotepine. These N-oxides were then subjected to well-established chemical transformations to test their oxidant properties in group VIII transition-metal-catalyzed reactions. In the osmium tetroxide catalyzed dihydroxylation of styrene or cinnamyl alcohol and in the tetrapropylammonium perruthenate catalyzed oxidation of cinnamyl alcohol, the benzepine N-oxides could be used as replacements for the standard oxidant, N-methylmorpholine N-oxide (NMO) with varying degrees of efficiency. From a chemical point of view, clozapine N-oxide displayed a comparable oxidation power to NMO, characterizing the benzepines as oxygen carriers. Moreover, quetiapine was found to be an excellent double oxygen acceptor, undergoing initial N-oxidation and subsequent S-oxidation. It is therefore worthwhile considering whether oxidative damage to the human body might be related to the potential redox properties of common antipsychotic drugs. Georg Thieme Verlag Stuttgart ? New York.
- Koerber, Jochen,Loeffler, Stefan,Schollmeyer, Dieter,Nubbemeyer, Udo
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p. 2875 - 2887
(2013/10/22)
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- A study of photodegradation of quetiapine by the use of LC-MS/MS method
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Photodegradation of quetiapine under UVC irradiation in methanol solution was investigated and structural elucidation of its photodegradation products was performed with the use of the reversed phase UHPLC system coupled with accurate mass hybrid ESI-Q-TO
- Skibinski, Robert
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experimental part
p. 232 - 240
(2012/04/10)
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- Behavioral approach to nondyskinetic dopamine antagonists: Identification of Seroquel
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A great need exists for antipsychotic drugs which will not induce extrapyramidal symptoms (EPS) and tardive dyskinesias (TDs). These side effects are deemed to be a consequence of nonselective blockade of nigrostriatal and mesolimbic dopamine D2 receptors. Nondyskinetic clozapine (1) is a low-Potency D2 dopamine receptor antagonist which appears to act selectively in the mesolimbic area. In this work dopamine antagonism was assessed in two mouse behavioral assays: antagonism of apomorphine-Induced climbing and antagonism of apomorphine-Induced disruption of swimming. The potential for the liability of dyskinesias was determined in haloperidol-Sensitized Cebus monkeys. Initial examination of a few close cogeners of I enhanced confidence in the Cebus model as a predictor of dyskinetic potential. Considering dibenzazepines, 2 was not dyskinetic whereas 2a was dyskinetic. Among dibenzodiazepines, 1 did not induce dyskinesias whereas its N-2-(2-Hydroxyethoxy)ethyl analogue 3 was dyskinetic. The emergence of such distinctions presented an opportunity. Thus, aromatic and N-Substituted analogues of 6-(piperazin-1-yl)-11H-Dibenz[b,e]azepines and 11-(piperazin-1-yl)dibenzo[b,f][1,4]-thiazepines and -Oxazepines were prepared and evaluated. 11-(4-[2-(2-Hydroxyethoxy)ethyl]-piperazin-1-yl)dibenzo[b,f][1,4]thiazepine (23) was found to be an apomorphine antagonist comparable to clozapine. It was essentially nondyskinetic in the Cebus model. With 23 as a platform, a number of N-Substituted analogues were found to be good apomorphine antagonists but all were dyskinetic.
- Warawa,Migler,Ohnmacht,Needles,Gatos,McLaren,Nelson,Kirkland
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p. 372 - 389
(2007/10/03)
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