Figure 3.

Representative time and dose dependence for reversal of established neuropathic pain in adult male mice by five newly synthesized P2Y₁₄R antagonists and reference compound 1. The drugs were injected 7 days post-sciatic nerve constriction. The paw withdrawal threshold (PWT) was determined using von Frey filaments applied to the postsurgical hindpaw.⁴¹ (A–D) Single injection (10 μmol/kg, p.o.) of a P2Y₁₄ R antagonist (active drug 15 or prodrugs 50 and 62–64) reversed the mechano-allodynia on the ipsilateral, nerve-injured hindpaw. (E, F) Reference antagonist 1 was compared to the potent antagonist 15, with both administered by oral gavage. A single p.o. administration (10 μmol/kg) of 1 or 15 reversed the mechano-allodynia. For all experiments, the drug injection had no effect on the contralateral hindpaw (B, F). Data were analyzed by twoway analysis of variance (ANOVA) with Dunnett’s comparisons, *P <0.05 versus day 0 and †P < 0.05 versus day 7. Data represent the mean ± SD. The vehicle used for the oral dosing consisted of 5% dimethyl sulfoxide (DMSO) + 10% (5% Kolliphor HS 15:DMSO, 5:95 by volume) in 0.5% methyl cellulose (0.2 mL dose). The vehicle used for the i.p. injection: 10% (5% Kolliphor HS 15:DMSO, 5:95 by volume) in saline (0.2 mL dose). Results with other antagonists (11, 15, and 16; i.p.) in the mouse CCI model are shown in Figure S8 (Supporting Information).