Central nervous system toxicities of chemotherapeutic agents.

Although there has been a significant progress in the recognition and management of the most common chemotherapy side effects, there is limited data on CNS toxicities. Since CNS toxicities can cause significant morbidity and delay or interruption of potentially effective therapies, there is a need for better understanding, early detection, prompt discontinuation of the offending drug, and use of antidotes when available. This review describes neurological toxicities from some of the commonly used chemotherapy agents.

9-Aminomethyl-9,10-dihydroanthracene (AMDA) analogs as structural probes for steric tolerance in 5-HT2A and H1 receptor binding sites.

Synthesis, radioligand binding and molecular modeling studies of several 9-aminomethyl-9,10-dihydroanthracene (AMDA) analogs were carried out to determine the extent of the steric tolerance associated with expansion of the tricyclic ring system and amine substitution at 5-HT(2A) and H(1) receptors. A mixture of (7,12-dihydrotetraphene-12-yl)methanamine and (6,11-dihydrotetracene-11-yl)methanamine in a 75-25% ratio was found to have an apparent K(i) of 10nM at the 5-HT(2A) receptor. A substantial binding affinity for (7,12-dihydrotetraphene-3-methoxy-12-yl)methanamine at the 5-HT(2A) receptor (K(i)=21 nM) was also observed. Interestingly, this compound was found to have 100-fold selectivity for 5-HT(2A) over the H(1) receptor (K(i)=2500 nM). N-Phenylalkyl-AMDA derivatives, in which the length of the alkyl chain varied from methylene to n-butylene, were found to have only weak affinity for both 5-HT(2A) and H(1) receptors (K(i)=223 to 964 nM). Our results show that large rigid annulated AMDA analogs can be sterically accommodated within the proposed 5-HT(2A) binding site.

Correlation of neurodevelopmental features and MRI findings in infantile Krabbe's disease.

OBJECTIVE: The purpose of our study was to compare MRI findings with neurobehavioral development in infants with Krabbe's disease. MATERIALS AND METHODS: Nine infants with Krabbe's disease underwent a total of 19 MR studies during the first year of life as well as tests of mental development, gross motor skills, and fine motor skills (score range: 0-100) within 1 month of imaging. MR scans were scored using the Loes severity scale based on signal abnormality and atrophy, ranging from 0 (best) to 32. We performed three comparisons (Student's t test): each test versus total brain Loes score, fine motor and gross motor tests versus Loes score for the pyramidal tract, and fine motor and gross motor tests versus Loes score for the internal capsule. RESULTS: Mean test results were 65+/-31 for mental development, 48+/-39 for gross motor score, 57+/-35 for fine motor score, and mean total brain score was 7.79+/-6.20. Correlations for total Loes score were -0.78 (p=0.003) for mental development, -0.74 (p=0.003) for gross motor function, and -0.80 (p<0.001) for fine motor function. Correlations for pyramidal system Loes scores were -0.73 (p=0.003) for fine motor function and -0.58 (p=0.028) for gross motor function. Correlation between Loes scores for internal capsule and fine motor function was -0.38 (p>0.05) and between Loes scores for internal capsule and gross motor function was -0.35 (p>0.05). CONCLUSION: The very good correlation between testing results and Loes scores for the entire brain and moderately good correlation between test results and scores for specific brain regions indicate the Loes scoring system likely provides a reasonable means for assessing prognosis and therapeutic response for infants with Krabbe's disease.

Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT(2A) receptor.

The effects of methoxy-substitution at the 1-, 2-, 3-, and 4-positions of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on h5-HT(2A) receptor affinity were determined. Racemic mixtures of these compounds were found to show the following affinity trend: 3-MeO > 4-MeO > 1-MeO approximately 2-MeO. Comparison of the effects of these substitutions, with the aid of computational molecular modeling techniques, suggest that the various positional and stereochemical isomers of the methoxy-substituted AMDA compounds interact differently with the h5-HT(2A) receptor. It is predicted that for the compounds with higher affinities, the methoxy oxygen atom is able to interact with hydrogen bond-donating sidechains within alternative h5-HT(2A) receptor binding sites, whereas the lower-affinity isomers lack this ability.

Structural determinants for high 5-HT(2A) receptor affinity of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (SpAMDA).

The synthesis and 5-HT(2A) receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3(')-pyrrolidine (4), a structurally unique tetracyclic 5-HT(2A) receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT(2A) receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT(2A) receptor affinities. In addition, the parent compound is shown to have high 5-HT(2) receptor selectivity.

Spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine-a structurally unique tetracyclic 5-HT2A receptor antagonist.

Structural elaboration of phenylethylamine to spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine (SpAMDA) produces an agent with unexpectedly high affinity (K(i)=4 nM) at 5-HT(2A) receptors. It was shown that SpAMDA acts as a 5-HT(2A) receptor antagonist. The structure and molecular geometry of SpAMDA are not consistent with existing pharmacophore features, and a novel 5-HT(2A) antagonist pharmacophore model is proposed for the binding of aminomethyl-9,10-dihydroanthracene analogs. Thus, SpAMDA may be a structurally novel parent of a new class of 5-HT(2A) receptor antagonists that binds to the receptor in a unique fashion that is distinct from the binding topology of existing 5-HT(2A) receptor antagonists.

Ring substituted analogues of 5-aminomethyl-10,11-dihydro-dibenzo[a,d]cycloheptene (AMDH): potential modes of binding to the 5-HT(2A) receptor.

The synthesis and 5-HT(2A) receptor affinities of 2-substituted-5-aminomethyl-10,11-dihydrodibenzo[a,d]cycloheptene (AMDH) derivatives are described. Comparison of the effects of substitution on affinities allowed assignment of potential binding modes in comparison with DOB-like agonists/antagonists and 3-substituted 1-(aminomethyl)-9,10-dihydroanthracene structures.

Geometry-affinity relationships of the selective serotonin receptor ligand 9-(aminomethyl)-9,10-dihydroanthracene.

With the exception of its two aromatic rings and basic nitrogen atom, 9-(aminomethyl)-9,10-dihydroanthracene (AMDA; 1) is remarkably devoid of the pharmacophore features usually associated with high-affinity receptor ligands such as the heteroatom hydrogen bonding features of the endogenous ligand serotonin. AMDA does contain a phenylethylamine skeleton within a tricyclic ring system, and the presence of the second aromatic group is necessary for optimal receptor affinity. The structural requirements for the binding of AMDA at 5-HT(2A) receptors were investigated with respect to the geometric relationship between the two aromatic rings. It appears that the geometry of the AMDA parent is in the optimal range for fold angle between aromatic moieties. Evaluation of conformationally constrained derivatives of AMDA suggests that a chain extended trans, gauche form is most likely responsible for high affinity.

Imaging-based integrative models of the heart: closing the loop between experiment and simulation.

We describe methodologies for: (a) mapping ventricular activation using high-density epicardial electrode arrays; (b) measuring and modelling ventricular geometry and fibre orientation at high spatial resolution using diffusion tensor magnetic resonance imaging (DTMRI); and (c) simulating electrical conduction; using comprehensive data sets collected from individual canine hearts. We demonstrate that computational models based on these experimental data sets yield reasonably accurate reproduction of measured epicardial activation patterns. We believe this ability to electrically map and model individual hearts will lead to enhanced understanding of the relationship between anatomical structure, and electrical conduction in the cardiac ventricles.