AI Article Synopsis
- Researchers developed new compounds by combining aripiprazole, an antipsychotic drug, with catecholamine-like structures from β-adrenoceptor agonists, resulting in novel hydroxy-substituted heteroarylpiperazines and homopiperazines that show high affinity for dopamine D receptors.
- Unlike aripiprazole, the new compounds effectively mimic dopamine interactions necessary for the receptor's active state, which helps recruit β-arrestin-2, a protein involved in signaling pathways.
- Some of these new ligands demonstrate biased agonism, showing lower activity in traditional receptor activation tests but preferring to activate β-arrestin-2 over G protein pathways, primarily due to the presence of an end
Article Abstract
By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the β-adrenoceptor agonists procaterol and BI-167107 (4), we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroarylhomopiperazines with high dopamine D receptor (DR) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the DR 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 DR 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.
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| http://dx.doi.org/10.1021/acs.jmedchem.7b00363 | DOI Listing |
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Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased DR Agonists.
J Med Chem
June 2017
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nuernberg, Schuhstraße 19, 91052 Erlangen, Germany.
Article Synopsis
- Researchers developed new compounds by combining aripiprazole, an antipsychotic drug, with catecholamine-like structures from β-adrenoceptor agonists, resulting in novel hydroxy-substituted heteroarylpiperazines and homopiperazines that show high affinity for dopamine D receptors.
- Unlike aripiprazole, the new compounds effectively mimic dopamine interactions necessary for the receptor's active state, which helps recruit β-arrestin-2, a protein involved in signaling pathways.
- Some of these new ligands demonstrate biased agonism, showing lower activity in traditional receptor activation tests but preferring to activate β-arrestin-2 over G protein pathways, primarily due to the presence of an end
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