The current Phase I SBIR Grant application by Inotek Pharmaceuticals Corporation proposes to test the antinociceptive effect of a novel A1 receptor agonist in rat models. As preliminary data we present evidence in cultured cells expressing various human Al receptor subtypes that the compound PJ8-75 is ultrapotent and ultraselective for the A1 adenosine receptor. Prior data indicate that adenosine, via the A1 receptor subtype, exerts antinociceptive effects. The current proposal will determine whether the applicants' A1 agonist compounds exert antinociceptive effects in vivo. The ligand will be administered intrathecally. The effect of the A1 agonist will be tested on thermo- and mechano-nociception in the carrageenan-induced acute hyperalgesia test and in the chronic traumatic neuropathy model (Seltzer) in rats. Minimally effective dose of the compound will be determined. In addition, combination approaches will be tested for antinociception. In the final aim we will conduct preliminary in-house toxicology studies with the compound. Efficacy of the ligand in the in vivo models, coupled with a benign toxicology profile, will trigger the Phase II SBIR Stage of the proposal, whereby formal toxicology and human safety and early efficacy evaluation will be conducted. ? ?
