The etiology of many debilitating neurological disorders including Parkinson's Disease, Huntington's disease and schizophrenia is associated with either an inadequate or excessive stimulation of central dopamine receptors. While drug molecules which act as dopamine agonists or antagonists may be clinically useful, the therapeutic picture has been complicated with the recent discovery of dopamine receptor sub-types, designated D1 and D2, which mediate distinct behavioral and peripheral responses.Therapeutic dopamine receptor ligands can only be maximally effective if they exhibit high receptor selectivity, which demands the elucidation of the physico/chemical properties of their binding sites. Aporphines are prototypical dopaminergic ligands but suffer from a lack of selectivity. It is the overall goal of this project to identify the physico/chemical nature of the region of the dopamine receptor that binds ring A of aporphinic dopaminergic ligands in both D1 and D2 subtypes to assist in the design of therapeutic agents with higher margins of clinical safety. To accomplish this goal: (1) eight novel hexahydroaporphine molecules containing cyclohexyl or bicyclic A rings will be synthesized in enantiomerically pure form. These molecules have been designed to interact in an agonist mode with D1 and/or D2 subtypes. A scheme which involves the acid-catalyzed cyclization of an appropriately substituted benzyloctahydroisoquinoline has been designed to provide the requisite aporphine 10,11-diol. Experience from preliminary studies in which bicyclic 10-monophenolic analogs were generated will facilitate the synthesis. (2) The affinity of each cyclohexyl and bicyclic molecule for D1 and D2 receptors will be assessed through radio-ligand binding studies and compared to its aromatic parent.Replacing the aromatic A ring of the aporphinic parents with the cyclohexyl or bicyclooctyl systems will increase hydrophobic bonding capabilities, while eliminating opportunity for van der Waals binding, permitting an assessment of the relative importance of each. In addition, the bicyclooctane system provides greater molecular bulk which allows an assessment of the importance of steric hindrance to A ring-receptor interaction.(3) Cyclohexyl and bicyclic ligands exhibiting high affinity for receptors will be evaluated for D1 and D2 agonist/antagonist activity utilizing biochemical indicators to determine the importance of hydrophobic interactions in eliciting each type of activity.
