Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure

Beitrag in einer Fachzeitschrift
(Originalarbeit)


Details zur Publikation

Autor(en): Möller D, Banerjee A, Uzuneser T, Skultety M, Huth T, Plouffe B, Hübner H, Alzheimer C, Friedland K, Müller CP, Bouvier M, Gmeiner P
Zeitschrift: Journal of Medicinal Chemistry
Verlag: AMER CHEMICAL SOC
Jahr der Veröffentlichung: 2017
Band: 60
Heftnummer: 7
Seitenbereich: 2908-2929
ISSN: 0022-2623


Abstract


1,4-Disubstituted aromatic piperazines are privileged structural motifs recognized by aminergic G protein-coupled receptors. Connection of a lipophilic moiety to the arylpiperazine core by an appropriate linker represents a promising concept to increase binding affinity and to fine-tune functional properties. In particular, incorporation of a pyrazolo[1,5-a]pyridine heterocyclic appendage led to a series of high-affinity dopamine receptor partial agonists. Comprehensive pharmacological characterization involving BRET biosensors, binding studies, electrophysiology, and complementation-based assays revealed compounds favoring activation of G proteins (preferably G(o)) over beta-arrestin recruitment at dopamine D-2 receptors. The feasibility to design G protein-biased partial agonists as putative novel therapeutics was demonstrated for the representative 2-methoxyphenylpiperazine 16c, which unequivocally displayed antipsychotic activity in vivo. Moreover, combination of the pyrazolo[1,5-a]pyridine appendage with a 5-hydroxy-N-propy1-2-aminotetraline unit led to balanced or G protein-biased dopaminergic ligands depending on the stereochemistry of the headgroup, illustrating the complex structure functional selectivity relationships at dopamine D2 receptors.



FAU-Autoren / FAU-Herausgeber

Alzheimer, Christian Prof. Dr.
Lehrstuhl für Physiologie
Banerjee, Ashutosh Dr.
Lehrstuhl für Pharmazeutische Chemie
Friedland, Kristina Prof. Dr.
Professur für Molekulare und Klinische Pharmazie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Huth, Tobias PD Dr. Dr.
Lehrstuhl für Physiologie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie
Müller, Christian P. Prof. Dr.
Professur für Suchtmedizin
Uzuneser, Taygun
Professur für Suchtmedizin


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


Autor(en) der externen Einrichtung(en)
Université de Montréal


Zitierweisen

APA:
Möller, D., Banerjee, A., Uzuneser, T., Skultety, M., Huth, T., Plouffe, B.,... Gmeiner, P. (2017). Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure. Journal of Medicinal Chemistry, 60(7), 2908-2929. https://dx.doi.org/10.1021/acs.jmedchem.6b01857

MLA:
Möller, Dorothee, et al. "Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure." Journal of Medicinal Chemistry 60.7 (2017): 2908-2929.

BibTeX: 

Zuletzt aktualisiert 2018-10-08 um 23:56