Dopamine has been implicated as the primary neurotransmitter associated with the psychomotor stimulant and reinforcing effects of many drugs of abuse, such as cocaine, methamphetamine and the opioids. These findings have resulted in intensive efforts to characterize and elucidate the roles of the various dopamine receptor subtypes in the pharmacology and addiction liability of these abused drugs. In this pursuit, the dopamine D3R subtype has been intensively targeted. We initially used the classic D3R antagonist NGB 2904 as the template for our structural modifications to elucidate SAR and develop novel and selective D3R antagonists and partial agonists with drug-like physicochemical properties. To this end we discovered very selective D3R antagonists and partial agonists with D3R/D2R-selectivites reaching >1000-fold. In addition, several of these analogues have been further screened for binding to receptors and ion channels and did not show significant binding affinities at any of these other (off) targets, highlighting that these agents are some of the most potent and selective D3R-antagonists and partial agonists reported to date. Moreover, the (+)- and (-)-enantiomers of several of our 3-OH analogues have been synthesized using enantioselective synthetic strategies or chiral chromatography and demonstrated enantioselectivity at D3R (>10-fold), but not significantly (<2-fold) at D2Rs. This was the first demonstration of enantioselectivity of a D3R antagonist and further chimera studies, with these enantiomers, identified an extracellular loop (E1) region that appears to differ between D3R and D2R. We have more recently combined small molecule SAR with the D3 receptor crystal structure solved with the D2-like antagonist eticlopride to design our newest generation of D3R-selective compounds. We hypothesized that the 2,3-diCl- or 2-OCH3-substituted-4-phenylpiperazine terminus, defined as the primary pharmacophore (PP), binds within the orthosteric binding site (OBS) of both the D2R and D3Rs, while the indole amide terminus termed as the secondary pharmacophore (SP), binds in a secondary binding pocket (SBP) at the interface of transmembrane domains (TMs) 1, 2, and 7 and the EL1, EL2, that significantly differ from the D2R. Site-directed mutagenesis studies have identified a single amino acid (Gly94) in the EL1 that differs between D2 and D3 receptors and is critically important for subtype selectivity. These studies have provided a structural basis for the contribution of the each component in these molecules to the binding and functional efficacy at D3R, and to the relative orientation of the primary and secondary pharmacophores for optimal D3R binding affinity, selectivity and efficacy. We reasoned that if we replaced the 2,3-diCl-phenylpiperazine with substitutions borrowed from the eticlopride structure that the new templates might serve as PPs with potentially improved D3R affinities, selectivities and/or metabolic stability. Hence, we designed a hybrid PP, using the 2-Cl substituent from the 2,3-dichlorophenylpiperazine and the 3-ethyl group that gives rise to high affinity binding at D2R and D3R to give 2-chloro-3-ethylphenylpiperazine. In addition, we incorporated another privileged D3R PP, the 2-methoxyphenylpiperazine, into our design to make the 3-chloro-5-ethyl-2-methoxyphenylpiperazine, which includes all but the 2-OH substituent from eticlopride and the 5-chloro-6-methoxy substituent found in both eticlopride and raclopride. Further, we explored the SP with different heteroaryl amides, as well as investigating the 2- or 3-OH or 3-F-substituted butyl linking chain. SAR was developed that demonstrates these new PPs can yield highly selective D3R antagonists, (e.g. VK4-116) which show promising behavioral results in rodent models of the prescription opioid, oxycodone abuse. VK4-116 is also more metabolically stable than our previous lead compound, PG648, and appears to reduce acquisition to oxycodone self administration suggesting that it might be useful as a treatment for opioid dependence, but also may be useful in preventing prescription opioid addiction when long term treatment is necessary for chronic pain. Further development of this compound as well as other lead molecules is underway.
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