Central and peripheral actions of the novel kappa-opioid receptor agonist, EMD 60400.

1. The pharmacological characteristics of the kappa-opioid receptor agonist, EMD 60400, have been investigated, with particular reference to its central and peripheral sites of action and its ability to influence nociception. The kappa agonists ICI 197067 and ICI 204448 were tested for purposes of comparison. 2. EMD 60400 and ICI 197067 bind with high affinity (IC50 values of 2.8 and 1.5 nM, respectively) and high selectivity to kappa-opioid receptors. ICI 204448 has a lower binding affinity (IC50 13.0 nM) and selectivity for kappa-opioid receptors. 3. EMD 60400, ICI 197067, and ICI 204448 are full and potent agonists in the rabbit vas deferens in vitro assay for kappa-opioid receptors (IC50 values of 41.8, 15.7 and 15 nM, respectively). 4. Ex vivo binding experiments in mice revealed that EMD 60400 and ICI 197067 were well taken up after s.c. administration. Brain levels of EMD 60400 were lower than those of ICI 197067 at comparable doses, indicating that EMD 60400 does not penetrate into the CNS as well as ICI 197067. 5. Haloperidol-induced DOPA accumulation in the nucleus accumbens of the rat was dose-dependently reversed by s.c. application of EMD 60400 and ICI 197067 at doses of and above 3 and 0.3 mg kg-1, respectively. ICI 204448 had no effect on DOPA accumulation at 30 mg kg-1, s.c.(ABSTRACT TRUNCATED AT 250 WORDS)