Functionally Selective Dopamine D2, D3 Receptor Partial Agonists

• Published in: Journal of medicinal chemistry Vol. 57; no. 11; pp. 4861 - 4875
• Main Authors: Möller, Dorothee, Kling, Ralf C, Skultety, Marika, Leuner, Kristina, Hübner, Harald, Gmeiner, Peter
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.06.2014; Amer Chemical Soc
• Subjects: Animals; Antipsychotic Agents - chemical synthesis; Antipsychotic Agents - chemistry; Antipsychotic Agents - pharmacology; Arrestins - metabolism; beta-Arrestin 2; beta-Arrestins; Chemistry, Medicinal; CHO Cells; Cricetulus; Drug Partial Agonism; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; HEK293 Cells; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - pharmacology; Humans; Life Sciences & Biomedicine; Mice; Molecular Docking Simulation; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Pharmacology & Pharmacy; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Radioligand Assay; Receptors, Dopamine D2 - agonists; Receptors, Dopamine D3 - agonists; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Swine; PROTEIN-REGULATED INDUCER; MOLECULAR-DYNAMICS; SUPER-POTENT; 7 TRANSMEMBRANE RECEPTORS; NEURITE OUTGROWTH; CORTICAL PYRAMIDAL NEURONS; DENDRITIC SPINE DENSITY; ANTIPSYCHOTIC-DRUGS; BINDING; D3 RECEPTOR
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5004039

Dopamine D2 receptor-promoted activation of Gαo over Gαi 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 D2L, D2S, and D3 receptors. Measurement of [35S]GTPγS incorporation at D2S coexpressed with G-protein subunits indicated significant bias for promotion of Gαo1 over Gαi2 coupling for several test compounds. Functionally selective D2S activation was most striking for the carbaldoxime 8b (Gαo1, pEC50 = 8.87, E max = 65%; Gαi2, 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 D2S receptors. Ligand efficacy and selectivity between D2S and D3 activation were strongly influenced by regiochemistry and the nature of functional groups attached to the pyrazolo[1,5-a]pyridine moiety.