Adatanserin hydrochloride

Using sodium azide (NaN3)-induced anoxia plus aglycaemia as a model of chemically-induced ischemia in the hippocampal slice, we have evaluated the effects of the novel 5-HT(1A) partial agonist/5-HT(2) receptor antagonist adatanserin and the 5-HT(1A) receptor agonist BAYx3702 on the efflux of endogenous glutamate, aspartate and GABA. BAYx3702 (10-1000 nM) produced a significant (P<0.05) dose-related attenuation of ischemic efflux of both glutamate and GABA with maximum decrease being observed at 100 nM (73 and 69%, respectively). This attenuation was completely reversed by the addition of the 5-HT(1A) antagonist, WAY-100635 (100 nM). Similarly, adatanserin (10-1000 nM) produced a significant (P<0.05) dose-related attenuation in glutamate and GABA efflux with a maximum of 72 and 81% at 100 nM, respectively. This effect was completely reversed by the 5-HT(2A/C) receptor agonist, DOI but unaffected by WAY-100635. The 5-HT(2A) receptor antagonist MDL-100907 produced a comparable attenuation of glutamate when compared to adatanserin, while the 5-HT(2C) receptor antagonist, SB-206553, had no effect on ischemic efflux. None of these compounds significantly altered aspartate efflux from this preparation. In conclusion, the 5-HT(1A) receptor partial agonist 5-HT(2) receptor antagonist, adatanserin is able to attenuate ischemic amino acid efflux in a comparable manner to the full 5-HT(1A) agonist BAYx3702. However, in contrast to BAYx3702, adatanserin appears to produce it effects via blockade of the 5-HT(2A) receptor. This suggests that adatanserin may be an effective neuroprotectant, as has been previously demonstrated for full 5-HT(1A) receptor agonists such as BAYx3702.

This paper describes the development of a mass spectrometer-based, intelligent, programmable, sample-selection data acquisition system with two unique features. One is that the system allows automatic determination of the mass to charge ratio (m/z) of an unknown compound and the utilization of the molecular ion information to perform selective ion monitoring (SIM) experiments for quantitation. The other is its decision-making capability to select intelligently different samples and perform different experiments during data acquisition. These features were demonstrated by the application of the system to simultaneous screening for the microsomal stability and metabolite profiling of adatanserin. In this application, the data acquisition system continuously calculated the peak areas of adatanserin from SIM analyses of a batch of microsomal incubates stopped at various time points. Once the peak area of adatanserin had dropped to an arbitrarily predefined 60% of the initial value, the system made a decision to perform metabolite profiling of the sample. This decision initiated a series of automated operations, such as selecting a sample for re-analysis, changing the data acquisition time and liquid chromatographic gradient and switching the SIM mode to the data-dependent product ion scanning mode. The completed analysis of the batch of samples provided information both on the microsomal stability and on the metabolic profile of adatanserin. This simultaneous approach to investigating microsomal stability and metabolite profiling significantly increases the throughput for drug discovery support.