Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

Dopamine D-2 receptor-promoted activation of G alpha(o) over G alpha(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 D-3 receptors. Measurement of [S-35]GTP gamma S incorporation at D-2S coexpressed with G-protein subunits indicated significant bias for promotion of G alpha(o1) over G alpha(i2) coupling for several test compounds. Functionally selective D-2S activation was most striking for the carbaldoxime 8b (G alpha(o1), pEC(50) = 8.87, E-max = 65%; G alpha(i2), pEC(50) = 6.63, E-max = 27%). In contrast, the investigated 1,4-disubstituted aromatic piperazines (1,4-DAPs) behaved as antagonists for beta-arrestin-2 recruitment, implying significant ligand bias for G-protein activation over beta-arrestin-2 recruitment at D-2S receptors. Ligand efficacy and selectivity between D-2S and D-3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.