X RAY MAPPING OF DOPAMINE D2 AGONISTS

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This study is designed to "map" the three dimensional structure and electronic character of a series of dopamine agonists. The specific agonists will be chosen from classes of compounds that are known to have dopaminergic activity. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by the net aromic charges, electron density distribution, electrostatic potentials, and intermolecular interaction energies. To calculate these quantities, carefully measured experimental x-ray diffraction data will be collected on a selected set of dopamine agonists with selectivity for the D2 dopamine receptor. The specific compounds chosen for charge density analysis are: for the D2 dopamine receptor. The specific compounds chosen for charge density analysis are: (1)(+/-)-2-(N-phenlethyl-N-propyl)amino-5-hydroxytetralin hydrochloride (PPHT), a very potent D2 dopamine agonist. (2) R(-)-apomorphine hydrochloride, an compound used clinically in the treatment of Parkinson's disease. (3) pergolide methansulfonate, an ergoline derivative used in the treatment of Parkinson's disease. (4) bromocriptine methanesulfonate is the most widely known dopaminergic drug and is used to correct the long term complications of levodopa therapy in the treatment of Parkinson's disease (5) (-)-quinpirole hydrochloride was chosen because it is a selective D2 dopamine receptor agonist. It shows anti-tremor effects in monkeys with induced Parkinsonian traits. A molecular modeling study including a series of dopamine agonists known to bind to the D2 receptor is proposed. The study will involve determining the lowest energy conformation of the molecules beginning with the x-ray crystallographic coordinates or a structure build from the Tripos fragment library. The molecules will be docked into a protein model that contains information about the electrostatic interactions between the receptor and the drug molecules.