Novel Dopamine D3 Receptor Ligands

National Institute On Drug Abuse

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Abstract

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 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 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 have explored numerous substituted phenyl-piperazines as the PP as well as SP with different heteroaryl amides, and have further investigated the 3-substitution on the butyl linking chain and separated enantiomers of both the 3-OH and 3-F analogues, identifying new lead molecules for investigation in vivo. We have identified two lead molecules: VK4-116 and VK4-40, which show promising behavioral results in rodent models of opioid abuse. Both compounds are metabolically stable and reduce acquisition to oxycodone self-administration suggesting that they might be useful as treatments for opioid dependence, but also may be useful in preventing addiction to prescription opioids. Further development of these compounds as well as other lead molecules is underway. In addition to bitopic ligands directed toward antagonists and partial agonists, we have also focused on D3R full agonists, using PD128,907 and PF592,379 as parent molecules. We have recently discovered one of the most D3R-selective ligands to date which emphasized the critical role of chirality in both the PP and linker.