Design, Synthesis and Evaluation of Molecules with Selective and Poly-Pharmacological Actions at D1R, D3R and Sigma Receptors

The dopamine D3 receptor (D3R) is one of the most studied receptors involved in drug addiction. One of the most common strategies to treat substance use disorders is via D3R antagonism. The majority of the D3R antagonists synthesized so far have poor pharmacokinetic properties and/or lack selectivity toward D3R. In this thesis, the design, synthesis and biological evaluation of novel molecules that target the dopamine D1 receptor (D1R), D3R and the serendipitous discovery of molecules that target s receptors will be described. Chapter 1 presents a survey of the fundamental pharmacology of D1R, D3R and s receptors and the therapeutic importance of ligands that target these receptors. In Chapter 2, a new series of D3R ligands was designed and synthesized. This series contains a classical D3R pharmacophore comprising an amine-containing “head” moiety, a hydrocarbon linker “body” and an arylamide “tail” region. Variations in the tetrahydroisoquinoline-containing “head” motif and the arylamide “tail” region were examined. Meanwhile, in the hydrocarbon linker region an aryl ring was introduced. This series of analogues was subjected to binding and functional activity assays at dopamine receptors (D1R-D5R) in vitro. Data from this structure-activity relationship (SAR) study indicates that the introduction of an aryl moiety in the linker portion was beneficial for D3R affinity. D3R affinity was found to be sensitive to substitutions in the tail region and in the head region. A number of ligands with high D3R affinity (Ki = 1-5 nM) and selectivity (\u3e20-fold) versus other dopamine receptors were identified. Functional assays showed that these compounds function as D3R partial agonists. These compounds are interesting leads for further development as potent, selective and bioavailable experimental therapeutics that target D3R. Selective dopamine D1 receptor (D1R) partial agonists and dopamine D3 receptor (D3R) antagonists are two promising classes of compounds to fight drug addiction. Furthermore, studies of cocaine addiction in mice have shown that the combined stimulation of D1R and D3R is synergistic, in reducing cocaine seeking and cocaine rewarding effects. Hence, the production of molecules having D1R partial agonist/D3R antagonist polypharmacological activity is a novel approach to treat cocaine addiction. In this regard, the tetrahydroprotberberine (THPB) alkaloid stepholidine is a promising candidate because it is one of only a handful of molecules that displays the required polypharmacology. However, stepholidine and stepholidine analogs synthesized thus far are quite potent toward D1R but exhibit moderate affinity for D3R. In Chapter 3, we hypothesized that increasing the size of ring C of stepholidine from a 6-membered to a 7-membered ring by introducing a heteroatom (O, S or N) will promote high affinity interactions with both D1R and D3R. A synthetic scheme to synthesize such compounds was developed. Surprisingly, these compounds had no affinity for D1R or D3R. However, they possessed selective affinity for the σ1R