A COMPARISON OF CHOLINESTERASE DISTRIBUTION IN THE CEREBELLUM OF SEVERAL SPECIES *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65142/1/j.1471-4159.1964.tb06717.x.pd

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood–brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, logP, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%

Some effects of muscarinic cholinergic blocking drugs on behavior and the electrocorticogram

Results are presented for the effects of drugs with muscarinic cholinergic blocking actions, both central and peripheral (scopolamine and 1-hyoscyamine) and primarily peripheral (methyl atropine and methyl scopolamine), on conditioned avoidance behavior, spontaneous motor activity, and the ECG in the rat.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46397/1/213_2006_Article_BF02341261.pd

Identification of Novel Functional Inhibitors of Acid Sphingomyelinase

We describe a hitherto unknown feature for 27 small drug-like molecules, namely functional inhibition of acid sphingomyelinase (ASM). These entities named FIASMAs (Functional Inhibitors of Acid SphingoMyelinAse), therefore, can be potentially used to treat diseases associated with enhanced activity of ASM, such as Alzheimer's disease, major depression, radiation- and chemotherapy-induced apoptosis and endotoxic shock syndrome. Residual activity of ASM measured in the presence of 10 µM drug concentration shows a bimodal distribution; thus the tested drugs can be classified into two groups with lower and higher inhibitory activity. All FIASMAs share distinct physicochemical properties in showing lipophilic and weakly basic properties. Hierarchical clustering of Tanimoto coefficients revealed that FIASMAs occur among drugs of various chemical scaffolds. Moreover, FIASMAs more frequently violate Lipinski's Rule-of-Five than compounds without effect on ASM. Inhibition of ASM appears to be associated with good permeability across the blood-brain barrier. In the present investigation, we developed a novel structure-property-activity relationship by using a random forest-based binary classification learner. Virtual screening revealed that only six out of 768 (0.78%) compounds of natural products functionally inhibit ASM, whereas this inhibitory activity occurs in 135 out of 2028 (6.66%) drugs licensed for medical use in humans

Histoenzymology of the developing rat spinal cord.

Using histochemical methods the activity of acetycholinesterase, acid phosphatase and various dehydrogenases was investigated in the developing rat spinal cord. At the ninth embryonic day (E9) only the activity of the lactate dehydrogenase slow-moving isoenzymes was prominent in spinal neurons. Between E13 and E15 an increase was observed in the activity of most of the dehydrogenases and of acid phosphatase in motoneurons and posterior root ganglion cells. Between E15 and E17 acetylcholinesterase activity increased markedly. On E17 and E20, this enzyme was also detectable in anterior and posterior roots and in neurons of the intermediate grey matter. On E20, although all grey matter neurons were cytologically fully differentiated, their enzymatic content was found to be still incomplete. The prominent acid phosphatase reaction within laminae I and II, which is characteristic of the adult rat, was absent in the fetal spinal cord. These findings indicate that the spinal cord metabolism is predominantly anaerobic during the first two-thirds of gestation. The histoenzymological maturation of grey-matter neurons is delayed in comparison to their cytological differentiation. Furthermore, the ontogenesis of motoneuronal acetylcholinesterase activity correlates well with the development of motor activities in the rat fetus