Functionally Selective Dopamine D₂, D₃Receptor Partial Agonists

Abstract

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.

1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

“…In contrast, dopamine and the reference D 2 agonist quinpirole were potent agonists for the recruitment of β-arrestin-2 (EC 50 180 nM and 51 nM, respectively, data not shown) under these assay conditions 22. …”

“…22 Ci/mmol, PerkinElmer, Rodgau, Germany) incubation was continued for another 75 min at 37 °C (30 min for D 2S + Gα o1 ). The equilibration was terminated by filtration through Whatman GF/B filters soaked with ice cold PBS.…”

“…Moreover, the analysis of steric properties revealed a preference for comparatively small lipophilic moieties, directing our interest to unsubstituted pyrazolo[1,5-a]pyridines. This is of special interest, since earlier investigations on dopamine D 2 -ligands favored hydrophilic substitution at the pyrazolo[1,5-a]pyridine core, for example by the addition of oxime or carbaldehyde groups 22,32. Furthermore, analysis of the hydrophilic properties suggested a possible variability in the amount of methylene spacers between orthosteric and extended binding pocket-addressing regions.…”

Synthesis and evaluation of fluoro substituted pyridinylcarboxamides and their phenylazo analogues for potential dopamine D3 receptor PET imaging

“…27 However, in our experience, D3 ligands of this structural class also tend to bind to serotonin 5-HT 1A receptors in brain tissue. 28,29 In our endeavor to synthesize 18 F-labeled D3 receptor ligands suitable for PET studies, we further investigated structure-activity relationships (SARs), based upon two early http://dx.…”

“…27 However, in our experience, D3 ligands of this structural class also tend to bind to serotonin 5-HT 1A receptors in brain tissue. 28,29 In our endeavor to synthesize 18 (Fig. 1).…”