Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism

The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (<b>1</b>) as the primary pharmacophore. We found that substitutions in the <i>N</i>-1- and/or <i>N</i>-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G_i/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound <b>19</b> was identified as a new lead for its selective D₂ G-protein biased agonism with an EC₅₀ in the subnanomolar range. Structure–activity correlations were observed between substitutions in positions <i>N</i>-1 and/or <i>N</i>-5 of <b>1</b> and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D₂R-BRET functional assays

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

Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D₂ Receptor (D₂R) Biased Agonism

The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (<b>1</b>) as the primary pharmacophore. We found that substitutions in the <i>N</i>-1- and/or <i>N</i>-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by G_i/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound <b>19</b> was identified as a new lead for its selective D₂ G-protein biased agonism with an EC₅₀ in the subnanomolar range. Structure–activity correlations were observed between substitutions in positions <i>N</i>-1 and/or <i>N</i>-5 of <b>1</b> and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D₂R-BRET functional assays

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

Novel and High Affinity 2‑[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as <b>11b</b>, which demonstrated high DAT affinity (<i>K</i>_i = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that <b>11b</b> may be a potential lead for development as a psychostimulant abuse medication

Novel and High Affinity 2‑[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

The development of pharmacotherapeutic treatments of psychostimulant abuse has remained a challenge, despite significant efforts made toward relevant mechanistic targets, such as the dopamine transporter (DAT). The atypical DAT inhibitors have received attention due to their promising pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl rings, and/or functionalizing the terminal nitrogen with substituted piperazines, resulting in several novel leads such as <b>11b</b>, which demonstrated high DAT affinity (<i>K</i>_i = 2.5 nM) and selectivity without producing concomitant locomotor stimulation in mice, as compared to cocaine. These results are consistent with an atypical DAT inhibitor profile and suggest that <b>11b</b> may be a potential lead for development as a psychostimulant abuse medication

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