title: Effects of GR-89696 and the novel peripherally selective OP2 agonists, EMD-61569 and EMD-61747, against focal cerebral ischemia in the rat.
abstract: We examined whether increases in blood-brain barrier (BBB) permeability occurring after stroke can be exploited to apply protective substances selectively to ischemic tissue. To do this, the actions of the peripherally selective OP2 agonists, EMD-61569 and EMD-61747, have been compared with those of the centrally acting OP2 agonist, GR-89696, in the rat permanent focal ischemia model. EMD-61569, EMD-61747 and GR-89696 all bound with high affinity to OP2 receptors and were potent agonists in the rabbit vas deferens functional assay. These substances also potently inhibited electrically-induced overflow of dopamine from slices of rat nucleus accumbens. EMD-61747 and EMD-61569 penetrate poorly into the CNS under normal conditions and reverse haloperidol-induced L-DOPA accumulation in the nucleus accumbens of the rat only at high doses, in contrast to GR-89696. Permanent unilateral occlusion of the middle cerebral artery (MCAO) was associated with a disruption of the BBB and an increase in the concentration of EMD-61747 in the area of the infarct. GR-89696 at a dose of 0.1 mg/kg s.c. produced a reduction in infarct volume by 38% after MCAO, EMD-61569 and EMD-61747 had no influence on swelling and ischemic damage. We conclude that EMD-61747 and EMD-61569 are potent OP2 agonists, which usually have a limited ability to penetrate the BBB. The change in the properties of the BBB in ischemic tissue was not sufficient to elicit neuroprotection, since both EMD-61747 and EMD-61569 were inactive in the focal ischemia model. Conversely, GR-89696 had a robust protective action, and probably powerful OP2-typical side effects as a consequence of its unrestricted central activity.
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy; D002545:Brain Ischemia / Q000188:drug therapy*; D002536:Cerebral Arteries / Q000187:drug effects / Q000502:physiology; D007980:Levodopa / Q000737:chemistry; D008026:Ligation; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology*; D011759:Pyrrolidines / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000819:agonists*