Department of Chemistry and Pharmacy, Medicinal Chemistry, and ‡Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Emil Fischer Center, Friedrich Alexander University , Schuhstrasse 19, 91052 Erlangen, Germany.
J Med Chem. 2014 Jun 12;57(11):4861-75. doi: 10.1021/jm5004039. Epub 2014 May 23.
Dopamine D2 receptor-promoted activation of Gα(o) over Gα(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 [(35)S]GTPγS incorporation at D(2S) coexpressed with G-protein subunits indicated significant bias for promotion of Gα(o1) over Gα(i2) coupling for several test compounds. Functionally selective D(2S) activation was most striking for the carbaldoxime 8b (Gα(o1), pEC50 = 8.87, E(max) = 65%; Gα(i2), 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 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.
多巴胺 D2 受体促进 Gα(o)对 Gα(i)的激活可能增加突触可塑性，从而改善精神分裂症的阴性症状。合成了包含吡唑并[1,5-a]吡啶部分的杂环多巴胺替代物，并研究了它们的结合特性，当以低至亚纳摩尔 K(i)值测定 D(2L)、D(2S)和 D3 受体时。在与 G 蛋白亚基共表达的 D(2S)上测量 [(35)S]GTPγS 掺入表明，几种测试化合物对 Gα(o1)与 Gα(i2)偶联的促进具有显著的偏向性。对于 carbaldoxime 8b（Gα(o1)，pEC50 = 8.87，E(max) = 65%；Gα(i2)，pEC50 = 6.63，E(max) = 27%），功能选择性 D(2S)激活最为明显。相比之下，研究的 1,4-取代的芳基哌嗪（1,4-DAPs）表现为β-arrestin-2 募集的拮抗剂，这意味着在 D(2S)受体上，与β-arrestin-2 募集相比，配体对 G 蛋白激活具有显著的配体偏向性。D(2S)和 D3 激活之间的配体功效和选择性强烈受到区域化学和连接到吡唑并[1,5-a]吡啶部分的官能团的性质的影响。
