| This dissertation describes the pharmacological and structural analysis of a novel class of compounds (benzo(a) phenanthridines) that were designed to act at dopamine receptors. The prototype of this class, termed dihydrexidine (DHX), was shown to be a high potency, bioavailable, full efficacy D{dollar}sb1{dollar} receptor agonist. While this ligand also possessed moderate D{dollar}sb2{dollar} affinity, it was shown to be highly selective for dopamine receptors. It appears that DHX acts by direct receptor activation rather than by indirect effects at either the dopamine uptake site or in the release of dopamine from the nerve terminal. In addition to its utility as a novel pharmacological tool to study D{dollar}sb1{dollar} receptor function, this ligand and related analogs of the benzo (a) phenanthridine class were used to define the structure-activity requirements (SAR) of D{dollar}sb1{dollar} receptors. Based on the SAR data, it was proposed that steric and/or electronic considerations around the amine binding site on the D{dollar}sb1{dollar} receptor are crucial to agonist activity, as is the positioning of the hydroxyl groups on the catechol ring. SAR analysis also demonstrated the importance of an accessory ring system on the agonist for D{dollar}sb1{dollar} receptor potency, efficacy and selectivity. The SAR studies of this rigid class were complimented with molecular modeling analysis to assess the D{dollar}sb1{dollar} receptor pharmacophore geometry and recognition site topography. Based on the agonist conformational analysis, it was hypothesized that DHX and other full efficacy agonists may share a D{dollar}sb1{dollar} pharmacophore made up of two hydroxyl groups, a nitrogen atom (ca. 7 A from the meta hydroxyl) and an accessory ring system (ca. 5 A from, slightly above, and close to planarity with the catechol ring). The topography of the receptor subsequently was mapped, and a detailed three-dimensional model of the D{dollar}sb1{dollar} receptor was proposed. Interestingly, DHX and N-propyl-DHX showed unique activity at D{dollar}sb2{dollar} dopamine receptors; they were able to activate D{dollar}sb2{dollar} receptors that are located postsynaptically, but unable to stimulate those D{dollar}sb2{dollar} receptors that are localized on the presynaptic terminal (i.e., autoreceptors). The results described in this dissertation demonstrate that the benzo (a) phenanthridine class (e.g., DHX) will provide powerful tools to generate and explore new hypotheses about dopamine receptors and their evolving roles in dopaminergic neurotransmission. |
