Neuroprotective and behavioral effects of the selective metabotropic glutamate mGlu(1) receptor antagonist BAY 36-7620

This study characterized the neuroprotective and behavioral effects of (3aS ,6aS)-6a-naphtalen-2-ylmethyl-5-methyliden-hexahydrocyclopenta[c]furan-1-on (BAY 36-7620), a novel, selective and systemically active metabotropic glu tamate (mGlu(1)), receptor antagonist. In the rat, neuroprotective effects were obtained in the acute subdural hematoma model (efficacy of 40-50% at 0 .01 and 0.03 mg/kg/h, i.v. infusion during the 4 h following surgery); wher eas in the middle cerebral artery occlusion model, a trend for a neuroprote ctive effect was obtained after triple i.v. bolus application of 0.03-3 mg/ kg, given immediately, 2 and 4 h after occlusion. Hypothermic effects were mild and only obtained at doses which were considerably higher than those a t which maximal neuroprotective efficacy was obtained, indicating that the neuroprotective effects are not a consequence of hypothermia. BAY 36-7620 p rotected against pentylenetetrazole-induced convulsions in the mouse MED: 1 0 mg/kg, i.v.). As assessed in rats, BAY 36-7620 was devoid of the typical side-effects of the ionotropic glutamate (iGlu) receptor antagonists phency clidine and (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)cyclohepten-5,10-im ine MK-801). Thus, BAY 36-7620 did not disrupt sensorimotor gating, induce phencyclidine-like discriminative effects or stereotypical behavior, or fac ilitate intracranial self-stimulation behavior. Although behavioral stereot ypies and disruption of sensorimotor gating induced by amphetamine or apomo rphine were not affected by BAY 36-7620, the compound attenuated some behav ioral effects of iGlu receptor antagonists, such as excessive grooming or l icking, and their facilitation of intracranial self-stimulation behavior. I t is concluded that mGlu(1) receptor antagonism results in neuroprotective and anticonvulsive effects in the absence of the typical side-effects resul ting from antagonism of iGlu receptors. (C) 2001 Elsevier Science B.V. All rights reserved.