Date of Award

Summer 1999

Document Type

Thesis

Degree Name

Master of Science in Applied Chemistry - (M.S.)

Department

Chemical Engineering, Chemistry and Environmental Science

First Advisor

Carol A. Venanzi

Second Advisor

David S. Kristol

Third Advisor

Tamara M. Gund

Abstract

Comparative Molecular Field Analysis (CoMFA) was performed on 30 methylphenidate analogues having phenyl ring substituents at the 2-, 3-, and 4-positions in an attempt to explain the structure-activity relationships of the analogues. Several CoMFA studies were carried out using different conformations of methylphenidate as the template structures for the corresponding alignment rules. The identification of the bioactive conformation was variously based on the interfeature distances in WIN 35,428, on cluster analysis, and on a comparison of active methylphenidate analogues. The sensitivity of the models to various CoMFA parameters was compared. These parameters included altering the size and spacing of the CoMFA grid, and changing different run-time CoMFA standards such as the steric and electrostatic energy cutoffs, and the column filtering value. Predictions of "novel", yet-to-be-synthesized methylphenidate analogues and of test sets of analogues were carried out using different models. The results showed that the q 2 of a model is affected most by the template structure, followed (in order of decreasing effect on q2) by the energy cutoffs, the column filtering value, and grid spacing and region box parameters. It was found that the 2-position analogues have poor IC50 values because they protrude into a sterically unfavorable region. Based on the CoMFA studies performed, a novel compound, 3,4-Br methylphenidate, has been suggested for synthesis and testing.

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