CR665 displays unmatched peripheral selectivity in animal models when compared to first generation kappa compounds. CR665 is intrinsically poor at penetrating the blood-brain barrier, which decreases the likelihood of CNS-mediated side effects. The peripheral selectivity of CR665 was evaluated in rodents by comparing the 50% effective dose (i.e., A ₅₀ value) to reduce viscero-somatic pain versus the 50% effective dose to induce a CNS-mediated effect. Pain was measured by the number of writhing movements after administration of an irritant into the abdomen, while the CNS effects were determined by impairment of motor coordination (inability to balance on a rotating horizontal rod). As shown (figure), previously developed kappa agonists such as enadoline, asimadoline, and TRK-820 inhibited the pain response at doses only 2- to 8-fold less than those producing an impairment of motor coordination in rodents. CR665, in contrast, showed a much larger safety margin with greater than 500-fold separation of doses required to produce analgesia versus CNS side effect.