Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (<i>R</i>)-<i>N</i>-(4-(4-(2,3-dichlorophenyl)­piperazin-1-yl)-3-hydroxybutyl)­1<i>H</i>-indole-2-carboxamide (<b>(</b><i><b>R</b></i><b>)-PG648</b>) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, <b>BAK 2-66</b>. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with <i>N</i>,<i>N</i>-diethylaminosulfur trifluoride (DAST). <b>(</b><i><b>R</b></i><b>)-BAK2-66</b> showed higher D3R affinity and selectivity than its (<i>S</i>)-enantiomer; however, it had lower D3R affinity and enantioselectivity than <b>(</b><i><b>R</b></i><b>)-PG648</b>. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-product (<b>8</b>)

Highly Selective Dopamine D₃ Receptor (D₃R) Antagonists and Partial Agonists Based on Eticlopride and the D₃R Crystal Structure: New Leads for Opioid Dependence Treatment

The recent and precipitous increase in opioid analgesic abuse and overdose has inspired investigation of the dopamine D₃ receptor (D₃R) as a target for therapeutic intervention. Metabolic instability or predicted toxicity has precluded successful translation of previously reported D₃R-selective antagonists to clinical use for cocaine abuse. Herein, we report a series of novel and D₃R crystal structure-guided 4-phenylpiperazines with exceptionally high D₃R affinities and/or selectivities with varying efficacies. Lead compound <b>19</b> was selected based on its in vitro profile: D₃R <i>K</i>_i = 6.84 nM, 1700-fold D₃R versus D₂R binding selectivity, and its metabolic stability in mouse microsomes. Compound <b>19</b> inhibited oxycodone-induced hyperlocomotion in mice and reduced oxycodone-induced locomotor sensitization. In addition, pretreatment with <b>19</b> also dose-dependently inhibited the acquisition of oxycodone-induced conditioned place preference (CPP) in rats. These findings support the D₃R as a target for opioid dependence treatment and compound <b>19</b> as a new lead molecule for development

Synthesis and Pharmacological Characterization of Novel <i>trans</i>-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D₃ Receptor (D₃R)

The development of bitopic ligands directed toward D₂-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D₃ receptor (D₃R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D₃R-selective antagonists SB269,652 (<b>1</b>) and SB277011A (<b>2</b>) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a <i>trans</i>-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D₃R-selective antagonists, <b>18a</b> and <b>25a</b>, which further delineates SAR associated with allosterism at D₃R and provides leads toward novel drug development

Synthesis and Pharmacological Characterization of Novel <i>trans</i>-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D₃ Receptor (D₃R)

The development of bitopic ligands directed toward D₂-like receptors has proven to be of particular interest to improve the selectivity and/or affinity of these ligands and as an approach to modulate and bias their efficacies. The structural similarities between dopamine D₃ receptor (D₃R)-selective molecules that display bitopic or allosteric pharmacology and those that are simply competitive antagonists are subtle and intriguing. Herein we synthesized a series of molecules in which the primary and secondary pharmacophores were derived from the D₃R-selective antagonists SB269,652 (<b>1</b>) and SB277011A (<b>2</b>) whose structural similarity and pharmacological disparity provided the perfect templates for SAR investigation. Incorporating a <i>trans</i>-cyclopropylmethyl linker between pharmacophores and manipulating linker length resulted in the identification of two bivalent noncompetitive D₃R-selective antagonists, <b>18a</b> and <b>25a</b>, which further delineates SAR associated with allosterism at D₃R and provides leads toward novel drug development

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor

Both dopamine D₃ receptor (D₃R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (<i>R</i>)-enantiomers are antagonists/weak partial agonists, whereas the (<i>S</i>)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D₃R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (<i>S</i>)-enantiomers, but not by the (<i>R</i>)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles

Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor

Both dopamine D₃ receptor (D₃R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably in efficacy: the (<i>R</i>)-enantiomers are antagonists/weak partial agonists, whereas the (<i>S</i>)-enantiomers are much more efficacious. To investigate the structural basis of partial agonism, we performed comparative microsecond-scale molecular dynamics simulations starting from the inactive state of D₃R in complex with these enantiomers. Analysis of the simulation results reveals common structural rearrangements near the ligand binding site induced by the bound (<i>S</i>)-enantiomers, but not by the (<i>R</i>)-enantiomers, that are features of partially activated receptor conformations. These receptor models bound with partial agonists may be useful for structure-based design of compounds with tailored efficacy profiles

Novel Analogues of (<i>R</i>)‑5-(Methylamino)-5,6-dihydro‑4<i>H</i>‑imidazo[4,5,1-<i>ij</i>]quinolin-2(1<i>H</i>)‑one (Sumanirole) Provide Clues to Dopamine D₂/D₃ Receptor Agonist Selectivity

Novel 1-, 5-, and 8-substituted analogues of sumanirole (<b>1</b>), a dopamine D₂/D₃ receptor (D₂R/D₃R) agonist, were synthesized. Binding affinities at both D₂R and D₃R were higher when determined in competition with the agonist radioligand [³H]­7-hydroxy-<i>N</i>,<i>N</i>-dipropyl-2-aminotetralin (7-OH-DPAT) than with the antagonist radioligand [³H]<i>N</i>-methylspiperone. Although <b>1</b> was confirmed as a D₂R-preferential agonist, its selectivity in binding and functional studies was lower than previously reported. All analogues were determined to be D₂R/D₃R agonists in both G_oBRET and mitogenesis functional assays. Loss of efficacy was detected for the <i>N</i>-1-substituted analogues at D₃R. In contrast, the <i>N</i>-5-alkyl-substituted analogues, and notably the <i>n</i>-butyl-arylamides (<b>22b</b> and <b>22c</b>), all showed improved affinity at D₂R over <b>1</b> with neither a loss of efficacy nor an increase in selectivity. Computational modeling provided a structural basis for the D₂R selectivity of <b>1</b>, illustrating how subtle differences in the highly homologous orthosteric binding site (OBS) differentially affect D₂R/D₃R affinity and functional efficacy