Novel Dopamine D3 Receptor Ligands

点击翻译按钮获取中文摘要

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. 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. 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. Further, we have investigated the composition and chirality of the linking chain and separated enantiomers of both the 3-OH and 3-F analogues, identifying new lead molecules for investigation in vivo and also discovering the critical role of the linker in the affinity, efficacy and functional selectivity of these novel ligands at D3R. 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. Separation of enantiomers to identify the R-enantiomer as the eutomer and development of these compounds as well as other lead molecules is underway toward clinical trials, in collaboration with NCATS. 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.