Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β‑Arrestin-Biased D₂R Agonists

By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β₂-adrenoceptor agonists procaterol and BI-167107 (<b>4</b>), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D₂ receptor (D₂R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D₂R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D₂R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands’ agonistic properties are substantially driven by the presence of an endocyclic H-bond donor

Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β‑Arrestin-Biased D₂R Agonists

By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β₂-adrenoceptor agonists procaterol and BI-167107 (<b>4</b>), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D₂ receptor (D₂R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the D₂R that are crucial for an active state, leading to the recruitment of β-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D₂R and consequently represent biased agonists favoring β-arrestin-2 recruitment over canonical G protein activation. The ligands’ agonistic properties are substantially driven by the presence of an endocyclic H-bond donor

Structure–Activity Study of <i>N</i>‑((<i>trans</i>)‑4-(2-(7-Cyano-3,4-dihydroisoquinolin-2(1<i>H</i>)‑yl)­ethyl)­cyclohexyl)‑1<i>H</i>‑indole-2-carboxamide (SB269652), a Bitopic Ligand That Acts as a Negative Allosteric Modulator of the Dopamine D₂ Receptor

We recently demonstrated that SB269652 (<b>1</b>) engages one protomer of a dopamine D₂ receptor (D₂R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within <b>1</b>. We find that orthosteric “head” groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of <b>1</b>, and replacement of the tetrahydroisoquinoline head group with other D₂R “privileged structures” generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D₂R

A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D₂ receptor (D₂R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D₂R partial agonist, <i>tert</i>-butyl (<i>trans</i>-4-(2-(3,4-dihydroisoquinolin-2­(1<i>H</i>)-yl)­ethyl)­cyclohexyl)­carbamate (<b>4</b>). This ligand shares structural similarity to cariprazine (<b>2</b>), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of <b>4</b> with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties