New pharmacological applications of dextromethorphan

Dextrometrophan (DM), an analogue of the morphinan opioid levorphanol, is an over-the-counter antitussive agent that has been used for several decades. The mechanisms of its antitussive effects are thought to be ascribed to the N-methyl-Daspartate (NMDA) receptors instead of the opioid receptors in the central nervous system. NMDA receptor is a kind of receptor that can be agonized by the excitory amino acids (EAAs), glutamate and aspartate, and employs NMDA as its most selective agonist. Many NMDA receptors are discovered not only in the central nervous system, but also in the peripheral nervous system and tissues with diverse physiological activities. As a noncompetitive antagonist of NMDA receptor, DM has been explored to treat other diseases in the animal models and clinical trials. This chapter discusses the new utilization of DM in the treatment of nervous and mental diseases, including pain relief, drug and nicotine withdrawal, epilepsy, Parkinson's disease, depression and pseudobulbar affect, as well as diabetes mellitus-related diseases. Most novel pharmacological applications of DM are based on the outcomes of randomized, doubleblind, placebo-controlled clinical trials rather than the validation of mechanisms in molecular and cellular pathways. DM is quickly metabolized to dextrophan by human CYP2D6 enzyme, which also occupies NMDA receptor antagonistic, a3ß4 nicotic receptor antagonistic and s-1 receptor agonistic activity with different potencies compared to DM. The mostly used strategy in clinic to improve the bioavailability and the portion of DM that is able to penetrate the blood brain barrier is the conjunct therapy with low-dose quinidine, a CYP2D6 inhibitor. More pharmacological activities of DM are gradually discovered with the elucidation of the distribution and function of central and peripheral NMDA receptors, and the efficacy of DM to agonize or antagonize other types of receptors.