Anticonvulsant activity of (+)‐5‐methyl‐10, 11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties

Abstract

MK‐801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED 50 being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ‐acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK‐801 was likewise the most potent (ED 50 = 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED 50 = 0.41 mg/kg p.o.) and MK‐801 (ED 50 = 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline‐elicited seizures in mice. Besides being a potent anticonvulsant, MK‐801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED 50 = 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED 50 > 15 mg/kg p.o.) than were needed against electroshock or bicuculline. The anticonvulsant (electroshock) effect of MK‐801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK‐801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α‐adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK‐801. Haloperidol was selective for MK‐801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK‐801. MK‐801 is an extremely potent and selective anticonvulsant acting at least partly via a catecholaminergic mechanism.