S1 Discovery of G Protein-Biased Dopaminergics with a Pyrazolo[1,5-a]pyridine Substructure Dorothee Möller, 1 Ashutosh Banerjee, 1 Taygun C. Uzuneser, 2 Marika Skultety, 1 Tobias Huth, 3 Bianca Plouffe, 4 Harald Hübner, 1 Christian Alzheimer, 3 Kristina Friedland, 5 Christian P. Müller, 2 Michel Bouvier, 4 Peter Gmeiner 1 * 1 Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany 2 Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany 3 Institute of Physiology and Pathophysiology, Friedrich-Alexander University Erlangen-Nürnberg, Universitätsstraße 17, 91054 Erlangen, Germany 4 Institute for Research in Immunology and Cancer (IRIC), Department of Biochemistry and Molecular Medicine, University of Montreal, Québec, Canada H3C 1J4 5 Department of Chemistry and Pharmacy, Molecular and Clinical Pharmacy, Friedrich-Alexander University Erlangen-Nürnberg, Cauerstraße 4, 91058 Erlangen, Germany SUPPORTING INFORMATION 1) Supplementary Figure 1. [ 35 S]GTPγS binding experiments with compounds 1a and 6a,b-9a,b. ……… S2 2) Supplementary Figure 2. D2SR-mediated β-arrestin-2 recruitment for 6a,b-9a,b and 12a-g……………. S3 3) Supplementary Figure 3. [ 35 S]GTPγS binding experiments with butoxy-spacer compounds…………… S4 4) Supplementary Figure 4. BRET² titrations for D2SR, D2LR and D3R …………………………………… S5 5) Supplementary Figure 5. Dose-response curves for D2SR activation determined by BRET…………….. S6 6) Supplementary Figure 6. Inhibition of quinpirole-induced β-arrestin-2 recruitment…………………..... S7 7) Supplementary Figure 7. D2LR or D3R mediated activation of GIRK1/2 channels.…………………..…. S8 8) Supplementary Figure 8. The effects of 16c compared to 1a on schizophrenia-like behavior in rats…… S9 9) Supplementary Table 1. D2LR and D3R activation characteristics determined by BRET……………….. S10 10) Supplementary Table 2. Quantification of ligand bias at D2SR using the operational model of agonism S11 11) Supplementary Results. The effects of 16c and 1a on schizophrenia-like behavior in rats: LIA………. S12 12) Supplementary Methods. Synthesis of compounds 3a,b; 4a,b; 5 and (R)/(S)-11……………………… S15 13) Supplementary Data. 1 H and 13 C NMR spectra of target compounds…………….……………………..S17 14) Supplementary References.…………………………………………………………………..………… S73