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Extra resources for Brain - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References
5) action because of the higher rate of enzymatic bioactivation after esterase cleavage of the protecting ester function. Analogues in which the carboxy-terminal prolinamide is replaced by L-pipecolic acid or the amino-terminal pyroglutaminyl residue is subtituted by an unnatural moiety will also be incorporated into appropriate targeting systems. 24 Brain The design and development will be supported by theoretical calculations. The newly designed analogs will be tested for binding to brain TRH receptors to compare their intrinsic activity with that of the lead compound.
Comparative pharmacodynamic evaluation of the effect of brain-delivered analogues will be addressed via in vivo cerebral microdialysis studies in which changes in acetylcholine levels due to treatment will be assayed. Ultimately, pharmacological experiments will be carried out in animals to survey the potential of the approach to treat maladies associated with the loss of cholinergic functions. The antagonism of pentobarbitalinduced sleeping will be used as general paradigm to assess the acute effects of braintargeted compounds.
To be able to use this strategy to improve brain drug uptake, a full understanding of the active site substrate specificity of this transport protein is necessary. To investigate our hypothesis, we will use a combination of physiological and computer modeling based methods. The in situ brain perfusion method will be used in adult rats to evaluate BBB transport processes. We have shown that N-n-octyl nicotinium iodide (NONI) binds and is transported by this transporter. Further, NONI significantly blocks nicotine's effects in brain dopamine systems in vitro.