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dc.contributor.authorHuang, Yu-Ing
dc.date.accessioned2013-04-03T20:03:02Z
dc.date.available2013-04-03T20:03:02Z
dc.date.issued1992
dc.identifier.urihttp://hdl.handle.net/10713/2504
dc.descriptionUniversity of Maryland, Baltimore. Biomedicinal Chemistry. Ph.D. 1992en_US
dc.description.abstractDiscovery of several venom toxins from spiders and a digger wasp as potent glutamate receptor antagonists has provided new approaches for the investigation of glutamate receptors. Philanthotoxin-433, a wasp toxin and an allosteric inhibitor of nicotinic acetylcholine (nAch) receptors, and numerous analogues have been reported to be potent antagonists of quisqualate receptors. In this dissertation, molecular mechanics and semiempirical (AM1) calculations were performed on 28 philanthotoxin (PhTX) analogues. Conformational analyses were carried out by systematic/grid searches to determine energy minima. In the calculated preferred conformations, two intramolecular hydrogen bonds were found to stabilize the conformers; one hydrogen bond between the two amides and another between the aromatic ring {dollar}\pi{dollar}-cloud and the polyamine chain amino hydrogens. Antagonistic potencies against the quisqualate and nAch receptors were explained through a spatial occupancy model of the PhTX analogues. Quantitative correlations were determined by comparative molecular field analyses (CoMFA). These studies revealed that the quisqualate receptor antagonism observed for the PhTX analogues correlated well with their structural modifications at the butyryl, tyrosyl and polyamine moieties. No significant correlation between the nAch receptor antagonism and PhTX structures was found. A CoMFA model for quisqualate receptor antagonism was established and had a correlation coefficient of 0.898 and a predictive r{dollar}\sp2{dollar} of 0.614. The logarithm of the IC{dollar}\sb{lcub}50{rcub}{dollar} values provided the best descriptor for the biological data in these CoMFA studies. The relative contribution of steric and electrostatic fields to the CoMFA model was 64% and 36%, respectively. A spermine chain with a free terminal amino functionality was found to be optimal for quisqualate receptor antagonism while the tyrosyl and butyryl moieties were predicted to be better regions for structural modifications leading to new antagonists.en_US
dc.language.isoen_USen_US
dc.subjectHealth Sciences, Toxicologyen_US
dc.subjectChemistry, Biochemistryen_US
dc.subjectHealth Sciences, Pharmacyen_US
dc.titleComputer-assisted analysis of structure-activity relationships of philanthotoxin analoguesen_US
dc.typedissertationen_US
dc.contributor.advisorCallery, Patrick S.
dc.contributor.advisorPou, Sovitj
dc.identifier.ispublishedYes
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