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

Journal article
(Original article)


Publication Details

Author(s): Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P
Journal: Journal of Medicinal Chemistry
Publisher: AMER CHEMICAL SOC
Publication year: 2017
Volume: 60
Journal issue: 11
Pages range: 4693-4713
ISSN: 0022-2623


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.



FAU Authors / FAU Editors

Dengler, Daniela
Lehrstuhl für Pharmazeutische Chemie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Männel, Barbara
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie
Shonberg, Jeremy
Lehrstuhl für Pharmazeutische Chemie


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


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.

BibTeX: 

Last updated on 2018-10-08 at 23:56