Drug screening in vivo If animal models are new, and reflect the disease state better, then they may allow different compounds to be selected if final compound selection is performed in the disease model. Thus very different, compounds will be chosen for drug development. The disease state may change the kinetics of receptor interactions or the multiple states of a receptor, meaning that screening #Linsitinib keyword# in normal conditions may not be appropriate. From thermodynamics, changing affinity by 100- to 1000-fold (ie, a enormous
change in structure-activity) may reflect a change in only one hydrogen bond between ligand and receptor, which is very difficult to predict, on a molecular level. Thus, it is likely that conformational modifications in a disease state – if the target is really a causative agent in the disease process – would involve changes of such a magnitude. Indeed, switching the conformation of a receptor
between agonist or antagonist states can change the affinity by more than Inhibitors,research,lifescience,medical a 1000-fold, entirely changing the structure-activity, because of changes in different binding pockets.1-3 Thus, differences between receptor ”states“ can be more important, than differences between types of Inhibitors,research,lifescience,medical receptor.2 It, is thus clear then that screening in appropriate disease Inhibitors,research,lifescience,medical models, rather than on putative receptor targets under normal conditions, would lead to drugs better targeted toward the pathological events, and thus toward better treatment, of the patient. It is also important to ensure that the same measures can be made in animals as in clinical testing. This may be easily accessible in the cardiovascular Inhibitors,research,lifescience,medical system, but studies in the central nervous
system (CNS) may require more indirect comparisons. However, some end points are amenable. We have studied electroencephalographic (EEG) techniques and extensively characterized means of transferring preclinical effects in conscious animals toward the same effects in man, as clinical ERG is a powerful means of defining the effects of drugs. Which models may be used for schizophrenia? Abnormalities in the neural circuits in the prefrontal cortex, which are involved in working memory, are the basis of the model of schizophrenia proposed by Goldman-Rakic,4,5 and have been seen in GPX6 imaging studies.6 A robust reduction (>3.5 million) in the number of thalamic neurones innervating frontal regions has been reported in subjects with schizophrenia.7 Thus, the prefrontal cortex is a key area and the hippocampus is also important because the ncurodcvelopmcnt model of schizophrenia indicates changes in its development.8,9 Phencyclidine (PCP) is an iV-methyl-D-aspartate (NMDA) antagonist that induces hallucinations in man.