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

Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P (2017)

Publication Status: Published

Publication Type: Journal article, Original article

Publication year: 2017

Journal

Publisher: AMER CHEMICAL SOC

Book Volume: 60

Pages Range: 4693-4713

Journal Issue: 11

DOI: 10.1021/acs.jmedchem.7b00363

Abstract

By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the beta(2)-adrenoceptor agonists procaterol and BI-167107 (4),, we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroatylhomopiperazines with high dopamine D-2 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 beta-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R. and consequently represent biased agonists favoring beta-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by thepresence of an endocyclic H-bond donor.

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How to cite

APA:

Männel, B., Dengler, D., Shonberg, J., Hübner, H., Möller, D., & Gmeiner, P. (2017). Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for beta-Arrestin-Biased D2R Agonists. Journal of Medicinal Chemistry, 60(11), 4693-4713. https://dx.doi.org/10.1021/acs.jmedchem.7b00363

MLA:

Männel, Barbara, et al. "Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for beta-Arrestin-Biased D2R Agonists." Journal of Medicinal Chemistry 60.11 (2017): 4693-4713.

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