Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

Möller D, Kling R, Skultety M, Friedland K, Hübner H, Gmeiner P (2014)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2014

Journal

Publisher: American Chemical Society

Book Volume: 57

Pages Range: 4861-4875

DOI: 10.1021/jm5004039

Abstract

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.

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APA:

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. https://dx.doi.org/10.1021/jm5004039

MLA:

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

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