Functionally selective dopamine D₂, D₃ receptor partial agonists.
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.
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.
Dorothee
D
Möller
Ralf C
RC
Kling
Marika
M
Skultety
Kristina
K
Leuner
Harald
H
Hübner
Peter
P
Gmeiner
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019390:Arrestins / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D054333:Drug Partial Agonism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D057809:HEK293 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000590790:5-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)pyrazolo(1,5-a)pyridine-3-carbaldehyde oxime; C000605254:ARRB2 protein, human; D014150:Antipsychotic Agents; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D006574:Heterocyclic Compounds, 2-Ring; D010091:Oximes; D010879:Piperazines; D011720:Pyrazoles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go