Synthesis and characterization of selective dopamine D2 receptor ligands using aripiprazole as the lead compound

Abstract

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D2-like dopamine receptors. These compounds also share structural elements with the classical D2-like dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D2 receptor subtype with high affinity (Ki values <0.3 nM), (b) exhibit >50-fold D2 versus D3 receptor binding selectivity and (c) be partial agonists at both the D2 and D3 receptor subtype.

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds

“…The studies presented in this communication represent continuation of our previous work on the development and pharmacological characterization of novel ligands that exhibit either D2 vs. D3 (Huang et al, 2013;Luedtke et al, 2012;Vangveravong et al, 2011Vangveravong et al, , 2010Vangveravong et al, , 2006 or D3 vs. D2 Tu et al, 2013Tu et al, , 2011Wang et al, 2010;Chu et al, 2005) dopamine receptor binding selectivity. It also extends our previous studies designed to use these dopamine D2-like receptor subtype selective compounds in vivo in an attempt to define the role of these two structurally and pharmacologically similar receptor subtypes in animal models of neurological and neuropsychiatric disorders (Kumar et al, 2009;Weber et al, 2009;Nolan et al, 2013;Rangel-Barajas et al, 2014), as well as psychostimulant abuse (Cheung et al, 2012.…”

“…Consequently, the initial pharmacologic binding profiles of the D2 and D3 dopamine receptor subtypes were found to be quite similar (Sokoloff et al, 1990;Boundy et al, 1993). However, over the last several years we have reported on the development of D2 vs. D3 (Vangveravong et al, 2006(Vangveravong et al, , 2010(Vangveravong et al, , 2011 and D3 vs. D2 dopamine receptor selective compounds (Chu et al, 2005;Tu et al, 2011).…”

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

“…Molecular modeling/docking techniques were then used to investigate the molecular parameters that might be responsible for the selective binding of SV 293 27 (Figures 9−11). Since SV-III-130s has a longer Table 2).…”

“…27 However, both SV 293 and SV-III-130s were found to be antagonists when the phosphorylation of ERK1/2 and coupling to GIRK channels was evaluated. This observation suggests a functional selectivity for SV-III-130s.…”

“…26 More recently, we synthesized a panel of aripiprazole analogues and identified several compounds with D2 versus D3 dopamine receptor binding selectivity. 27 In this report, we investigated the molecular basis for the binding selectivity of two D2 dopamine receptor selective compounds, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s). We have (a) further investigated the intrinsic efficacy of these two compounds, (b) compared the affinity of these compounds for both wild type D2 and D3 receptors and a panel of chimeric D2/D3 dopamine receptors, and (c) used computer-assisted modeling techniques to dock these compounds to our models of the D2 and D3 dopamine receptor subtypes 24 to further define the molecular basis for the observed receptor subtype binding selectivity.…”