Heterocyclic Analogues of N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with Functionalized Linking Chains as Novel Dopamine D3 Receptor Ligands:  Potential Substance Abuse Therapeutic Agents

Abstract

Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphenylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at the human dopamine D3 (hD3) receptor (Ki = 1-5 nM) as measured in competition binding assays. Several analogues showed >100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors, several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile.

Food Restriction Alters N′-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride (Pramipexole)-Induced Yawning, Hypothermia, and Locomotor Activity in Rats: Evidence for Sensitization of Dopamine D2 Receptor-Mediated Effects

“…Therefore, although decreases in D3 receptor function could explain the suppressed yawning response in food-restricted rats, increases in D2 receptor function and/or sensitivity would also be expected to suppress pramipexole-induced yawning. Support for the notion that food restriction induced changes in the D2 but not D3 receptor function and/or sensitivity was provided by the effects of the D3-selective PG01037 (ϳ133-fold selective for D3 over D2 receptors in vitro; Grundt et al, 2005Grundt et al, , 2007 and D2-selective L741,626 (ϳ13-fold selective for D2 over D3 receptors in vitro; Millan et al, 2000) antagonists on pramipexole-induced yawning.…”

Effects of Oral and Intravenous Administration of Buspirone on Food–Cocaine Choice in Socially Housed Male Cynomolgus Monkeys

“…The animal was observed to assure that he had eaten all of the banana. PG01037 was synthesized as described in Grundt et al (2007) at the National Institute on Drug Abuse-Intramural Research Program and dissolved in a vehicle of 40% b-cyclodextrin in sterile water.…”

“…To examine whether the predictive nature of preclinical models could be enhanced, a recent study in monkeys showed that 5 days of treatment with buspirone did not decrease cocaine selfadministration when studied under a food-cocaine choice paradigm, consistent with the clinical trials findings (John et al, 2014). In the present experiments, we extended these results by characterizing the effects of buspirone on the reinforcing strength of cocaine relative to food using a choice procedure in socially housed male cynomolgus monkeys and compared these effects with those of a highaffinity (K i ¼ 0.7, 93.3, and 375.0 nM at human hD 3 , D 2 , and D 4 receptors, respectively) and highly selective (133-fold versus D 2 and 540-fold versus D 4 receptors) D 3 receptor antagonist PG01037 (Grundt et al, 2007).…”

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

“…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).…”