Supplementary Materials

The PDF file includes:

• Materials and Methods
• Fig. S1. Generation of HEK-hNPR2-cGMP sensor cells.
• Fig. S2. hNPR1 inhibitors also block hNPR2.
• Fig. S3. JS-11 does not inhibit ACs.
• Fig. S4. In vivo pharmacokinetics of JS-11.
• Fig. S5. Effects of NPR1 antagonist on general motor behavior and itch responses.
• Fig. S6. JS-11 does not cause extensive cardiovascular side effects.
• Fig. S7. JS-11 inhibits itching in a mouse model of contact dermatitis.
• Fig. S8. General plate map layout for qHTS.
• Fig. S9. qHTS concentration response curves for JS-1 through JS-15.
• Table S1. Summary of qHTS and counterscreens.
• Table S2. Corroboration of hNPR1 inhibition in screening assay.
• Table S3. SafetyScreen44-dependent test for off-targets of JS-11.
• Table S4. Inhibition of hNPR1 in membrane cyclase assay.
• Table S5. K_i values for hNPR1 and mNPR1.
• Table S6. hNPR1 antagonists also inhibit mNPR1.
• Table S7. In vitro pharmacokinetics of JS-11 and JS-8.
• Table S8. PubChem AIDs deposited and used for this study.
• Table S9. Clinical information of human DRG donors.
• Legends for data files S1 to S4
• References (62–72)

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Other Supplementary Material for this manuscript includes the following:

• Data file S1 (Microsoft Excel format). LOPAC pilot screening data.
• Data file S2 (Microsoft Excel format). Genesis primary qHTS screening data.
• Data file S3 (Microsoft Excel format). qHTS follow-up screening data.
• Data file S4 (Microsoft Excel format). Raw data.