N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists

Abstract

In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl-and 2-OCH 3 -phenyl piperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R-and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K i =1 nM) for D3 and ∼400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders. Keywordsdopamine; D3 receptor; cocaine; drug abuse; addiction The dopamine D3 receptor, a member of the dopamine D2-like receptor family, has become a target of intensive research over the past decade due to several features that have revealed its potential for development of medications toward neuropsychiatric disorders, dyskinesias associated with L-DOPA treatment of Parkinson's disease, and drug addiction. [1][2][3] Numerous studies have been published that implicate the dopamine D3 receptors in animal models of these disorders. However, many of the pharmacological tools that have been available for in vivo investigation cannot rule out other possible underlying mechanisms of action, due to lack γ This manuscript is dedicated to the memory of my dear friend and colleague, Dr. Andrew Thurkauf, who first introduced me to the dopamine D3 receptor antagonists more than a decade ago. *anewman@intra.nida.nih.gov; phone: (443) 740-2887; Fax: (443) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of D3 receptor selectivity, poor bioavailability, or predicted toxicity that precludes human testing. Indeed, another complicating factor is that although functional coupling of D3 receptors to G αi/o -proteins has been established, 4,5 the question of which G-protein signaling pathways are recruited by D3 receptor activation in vivo remains unanswered.Nevertheless, the fact that several D3 antagonists have demonstrated efficacy in animal models of drug abuse without the concomitant motor side effects associated with nonselective D2 antagonists, supports further pursuit of the D3 receptor as a potential target for medication development. One of the single most important drivers of this research is the medicinal chemistry that has ultimately broken the barriers of nonselective D2/D3 ligands and enabled the discovery of high affi...

A Single Glycine in Extracellular Loop 1 Is the Critical Determinant for Pharmacological Specificity of Dopamine D2 and D3 Receptors

“…Similarly, modeling studies of the A 3 adenosine receptor in complex with an agonist containing rigid C2 extensions have suggested that an outward displacement of TM2 is required to accommodate such a bulky ligand (Tosh et al, 2012). Prior chimeric receptor and mutagenesis studies were consistent with a contribution of a region containing EL1 and, to a much lesser degree, EL2, in D3R over D2R selectivity for R-22 (Newman et al, 2009) and another highly D3R-selective F-analog of R-22 (Banala et al, 2011). The current results detail the specific contribution of EL1 to the D3R over D2R selectivity of R-22 and C4 analog, and identify Gly94 as the critical residue in D3R for this selectivity, through its ability to modulate the size and shape of the SBP and allow the SP to bind in Ptm23.…”

“…Notwithstanding these challenges, extensive medicinal chemistry efforts have led to the discovery of a class of 4-phenylpiperazine derivatives that is highly selective for D3R over D2R (e.g., compound R-22 [(R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide] has .100-fold selectivity for D3R over D2R) (Boeckler and Gmeiner, 2006;Newman et al, 2009). These D3R-selective compounds are characterized by a 4-phenylpiperazine primary pharmacophore (PP) and an extended aryl amide secondary pharmacophore (SP) connected by a 4-carbon linking chain (Heidbreder and Newman, 2010).…”

“…These D3R-selective compounds are characterized by a 4-phenylpiperazine primary pharmacophore (PP) and an extended aryl amide secondary pharmacophore (SP) connected by a 4-carbon linking chain (Heidbreder and Newman, 2010). Previous structure-activity relationship studies have attributed the subtype selectivity for D3R over D2R to the substituents on the 4-phenylpiperazine, an extended aryl amide ring system, and the length and functionalization of the linking chain (Grundt et al, 2007;Newman et al, 2009;Banala et al, 2011). Based on the crystal structure of D3R, we recently demonstrated that D3R over D2R selectivity mainly arises from divergent interactions of the SP within a second binding pocket (SBP) lined by residues from TMs 1, 2, 3, and 7, and extracellular loops 1 and 2 (EL1 and EL2, respectively) (Newman et al, 2012a).…”

What Can Crystal Structures of Aminergic Receptors Tell Us about Designing Subtype-Selective Ligands?

“…Previously, extensive medicinal chemistry efforts have led to the discovery of a class of 4-phenylpiperazine derivatives that is highly selective for D3R over D2R (e.g., compound R-22 [(R)-N-(4-(4-(2,3-dichlorophenyl) piperazin-1-yl)-3-hydroxybutyl)-1H-indole-2-carboxamide] has a .100-fold selectivity for D3R over D2R) (Boeckler and Gmeiner, 2006;Newman et al, 2009). These D3R-selective compounds are characterized by a 4-phenylpiperazine scaffold and an aryl amide moiety connected by a four-carbon linking chain (Heidbreder and Newman, 2010).…”

“…These D3R-selective compounds are characterized by a 4-phenylpiperazine scaffold and an aryl amide moiety connected by a four-carbon linking chain (Heidbreder and Newman, 2010). Based on previous studies (Ehrlich et al, 2009;Newman et al, 2009), we hypothesized that the 4-phenylpiperazine, the PP of R-22, would bind within the OBS of both D3R and D2R (Chien et al, 2010). This orientation of the PP positions the arylamide, the SP of R-22, in the SBP 237 (see section II.B), which can accommodate the SP in several distinct binding modes.…”