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

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): Männel B, Dengler D, Shonberg J, Hübner H, Möller D, Gmeiner P
Zeitschrift: Journal of Medicinal Chemistry
Verlag: AMER CHEMICAL SOC
Jahr der Veröffentlichung: 2017
Band: 60
Heftnummer: 11
Seitenbereich: 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-Autoren / FAU-Herausgeber

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


Zusätzliche Organisationseinheit(en)
Emil-Fischer-Zentrum (Emil Fischer Center)


Zitierweisen

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: 

Zuletzt aktualisiert 2018-10-08 um 23:56