Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

Beitrag in einer Fachzeitschrift

Details zur Publikation

Autor(en): Möller D, Kling R, Skultety M, Friedland K, Hübner H, Gmeiner P
Zeitschrift: Journal of Medicinal Chemistry
Verlag: American Chemical Society
Jahr der Veröffentlichung: 2014
Band: 57
Seitenbereich: 4861-4875
ISSN: 0022-2623
Sprache: Englisch


Dopamine D2 receptor-promoted activation of Gαo over Gαi may increase synaptic plasticity and thereby might improve negative symptoms of schizophrenia. Heterocyclic dopamine surrogates comprising a pyrazolo[1,5-a]pyridine moiety were synthesized and investigated for their binding properties when low- to subnanomolar Ki values were determined for D2L, D2S, and D3 receptors. Measurement of [35S]GTPγS incorporation at D2S coexpressed with G-protein subunits indicated significant bias for promotion of Gαo1 over Gαi2 coupling for several test compounds. Functionally selective D2S activation was most striking for the carbaldoxime 8b (Gαo1, pEC50 = 8.87, E max = 65%; Gαi2, pEC50 = 6.63, E max = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for β-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over β-arrestin-2 recruitment at D2S receptors. Ligand efficacy and selectivity between D2S and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety. © 2014 American Chemical Society.

FAU-Autoren / FAU-Herausgeber

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
Kling, Ralf
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie

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


Möller, D., Kling, R., Skultety, M., Friedland, K., Hübner, H., & Gmeiner, P. (2014). Functionally Selective Dopamine D2, D3 Receptor Partial Agonists. Journal of Medicinal Chemistry, 57, 4861-4875.

Möller, Dorothee, et al. "Functionally Selective Dopamine D2, D3 Receptor Partial Agonists." Journal of Medicinal Chemistry 57 (2014): 4861-4875.


Zuletzt aktualisiert 2018-11-07 um 22:10