X RAY MODELING OF DOPAMINE AGONISTS

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This project is designed to "map" the three dimensional structure and electronic character of a series of dopamine agonists. The mapping will include the overall geometry of the drug molecules as well as the electronic characteristics defined by the net atomic 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 varying degrees of pharmacological activity and receptor selectivity. These include compounds belonging to the aminotetralin, aporphine, ergoline, benzazepine, and benz[e]indole classes of compounds. The specific compounds chosen for charge density analysis are: (l) (+/-)-2-dipropylamino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide, one of the most potent dopaminergic aminotetralin derivatives known. (2) R(-)-morphothebaine hydrochloride, a dopaminergic aporphine derivative with mixed D1/D2 receptor selectivity. (3) pergolide methansulfonate, an ergoline derivative used in the treatment of Parkinson's disease. (4) (+/-)-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3- benzazepine hydrochloride, a centrally acting D1 dopamine agonist. (5) N-n-propyl-6-hydroxy-1,2,3a,4,5,9b-hexahydro-3H-benz[e]indole, a dopamine agonist with mixed D1/D2 receptor affinity. Using the results from the x-ray crystal structures of dopamine agonists not before determined, information regarding the three dimensional structure and conformation of the molecules will be obtained. These data will be used in an attempt to understand how small structural modifications can result in radical changes in pharmacological activity. To progress beyond a simple lock and key model, adding the electronic structure of the molecules determined experimentally from high resolution x-ray diffraction measurements allows a more complete description of the stereochemical, conformational, and electronic requirements of the dopamine receptor binding sites to be developed.