Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity

Abstract

Dizocilpine (MK-801), an extensively investigated drug possessing secondary amine and benzenoid functions, displays a wide array of biological properties, including anticonvulsant and anesthetic. There is scant discussion of biomechanism. A relevant, important finding is formation of oxidative metabolites in the hydroxylamine and phenolic categories. Analogy to cocaine metabolites suggests participation of redox entities, such as, hydroxylamine, nitroxide and nitrosonium, which can lead to electron transfer and radical formation. There is also similarity to metabolism by 3,3'-iminodipropionitrile and phencyclidine. Alternatively, the phenolic metabolites are well-known precursors of ET quinones. The review documents various physiological effects, mainly involving the central nervous system. Also of interest are the pro- and ant-oxidant properties. Considerable attention has been paid to MK-801 as an antagonist of the N-methyl-D-aspartate receptor in the glutamate category. This aspect is often associated with effects on the central nervous system. The review also provides recent literature dealing with MK-801/NMDA receptor in various areas of bioactivity. Studies were made of MK-801 involvement in working memory processing. Deficits in behavior were noted after administration of the drug. Treatment of mice with dizocilpine induced learning impairment. The influence of MK-801 on fear has been investigated. The substance is known to exert an analgesic effect in pain control. A number of reports deal with anesthetic properties.

Figure 1

Diazocilpine MK-801. This secondary-amine is addressed mainly in connection mechanism and physiological activity. Metabolism yields a hydroxylamine which may be associated with redox entities (Fig. 2), as in the case of cocaine. There is also similarity to 3,3′-iminodipropionitrile and phencyclidine. Mk-801 possesses a large number of physiological effects involving anesthesia, anticonvulsant, the CNS, memory, behavior, learning, fear and analgesia.

Figure 2

Phencyclidine and metabolites. Phencyclidine (PCP) (9a) has been extensively investigated as an abused drug. Mechanistic insight is gained from metabolic studies that show formation of iminium (9b). The electroreduction of 9b is facilitated by the aromatic nucleus despite lack of conjugation, indicating through space delocalization of the radical product. A computational report also supports this type of stabilization. MK-801 bears analogy by the presence ofa beta-nitrogen possessing radical character from electroreduction of nitrosonium.

Scheme 1

Cocaine metabolism. There is similarity to MK-801 in relation to involvement of a secondary-amine (4) with subsequent metabolism to a hydroxylamine (6). Various studies also report participation of nitroxide (3) and nitrosonium (7). There is evidence for redox cycling entailing ET process with subsequent formation of ROS in some cases. The CNS may be involved in the ET reactions. Toxicity might reflect harmful effects from ROS generation.