Effects of GR-89696 and the novel peripherally selective OP2 agonists, EMD-61569 and EMD-61747, against focal cerebral ischemia in the rat

We examined whether increases in blood-brain barrier (BBB) permeability occ urring after stroke can be exploited to apply protective substances selecti vely to ischemic tissue. To do this, the actions of the peripherally select ive OP2 agonists, EMD-61569 and EMD-61747, have been compared with those of the centrally acting OP2 receptors and were potent agonists in the rabbit vas deferens functional assay. These substances also potently inhibited ele ctrically-induced overflow of dopamine from slices of rat nucleus accumbens . EMD-61747 and EMD-61569 penetrate poorly into the CNS under normal condit ions and reverse haloperidol-induced L-DOPA accumulation in the nucleus acc umbens of the rat only at high doses, in contrast to GR-89696. Permanent un ilateral 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-61547 had no influence on swelling and ischemic damage. We conclude that EMD-61747 and EMD-61569 a re potent OP2 agonists, which usually have a limited ability to penetrate t he 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 we re inactive in the focal ischemia model. Conversely, GR-89696 had a robust protective action, and probably powerful OP2-typical side effects as a cons equence of its unrestricted central activity. (C) 1999 Prous Science. All r ights reserved.