Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

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• 作者：Dorothee M枚ller ; Ralf C. Kling ; Marika Skultety ; Kristina Leuner ; Harald H眉bner ; Peter Gmeiner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：June 12, 2014
• 年：2014
• 卷：57
• 期：11
• 页码：4861-4875
• 全文大小：551K
• 年卷期：v.57,no.11(June 12, 2014)
• ISSN：1520-4804

文摘

Dopamine D₂ receptor-promoted activation of G伪_o over G伪_i 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 K_i values were determined for D_2L, D_2S, and D₃ receptors. Measurement of [³⁵S]GTP纬S incorporation at D_2S coexpressed with G-protein subunits indicated significant bias for promotion of G伪_o1 over G伪_i2 coupling for several test compounds. Functionally selective D_2S activation was most striking for the carbaldoxime 8b (G伪_o1, pEC₅₀ = 8.87, E_max = 65%; G伪_i2, pEC₅₀ = 6.63, E_max = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for 尾-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over 尾-arrestin-2 recruitment at D_2S receptors. Ligand efficacy and selectivity between D_2S and D₃ activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.