|
Neurokinin 1 (NK1) antagonists are a novel class of medications that possesses unique antidepressant,〔()〕 anxiolytic, and antiemetic properties. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy. An example of a drug in this class is aprepitant. Chemotherapy-induced emesis appears to consist of acute and delayed phases. So far, the acute phase emesis responds to 5-HT3 antagonists while the delayed phase remains difficult to control. The discovery and development of NK1 receptor antagonists have elicited antiemetic effect in both acute and especially in delayed phases of emesis. Casopitant, netupitant and rolapitant are some newer additions in this group. Rolapitant has a significantly long half life of 160 hours and got approval by the USFDA in 2015. The first registered clinical use of NK1 receptor antagonists was the treatment of emesis, associated with cancer chemotherapy. == History == In 1931, von Euler and Gaddum discovered substance P (SP) in horse brain and intestine. The substance showed strong vasodilatory effects and contractile activity on the rabbit gut. A great effort was put into purifying this substance from diverse mammalian tissue, but 30 years of research were without success. Nonmammalian peptides that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early 1960s. These peptides had a common C-terminal sequence, and were grouped together as tachykinins. In 1971, Chang managed to purify SP from horse intestine and identify its amino acid sequence; SP was then classified as a mammalian tachykinin. In the 1970s, it became clear that SP was a neuropeptide that was common in the central and peripheral nervous system. In the mid 1980s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered. This led to further research, resulting in the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984, it was decided that the tachykinin receptors should be called tachykinin NK1 receptor, tachykinin NK2 receptor and tachykinin NK3 receptor.〔 Biological research that identified the many functions of tachykinins sparked interest in neurokinin receptor antagonists development.〔 In the 1980s, several peptide antagonists derived from SP were the first NK1 receptor antagonists. However, these compounds, like most peptide compounds, had problems with selectivity, potency, solubility and bioavailability. For this reason, pharmaceutical companies concentrated on developing non-peptide NK1 receptor antagonists, and in 1991, three different companies revealed their first results. Since then, non-peptide NK1 receptor antagonists have been researched extensively and many structures and patents have appeared. Proposing the concept in the early 1990s, in 1998 Kramer, ''et al.'', reported clinical data on the efficacy and safety of MK-869 (aprepitant) in patients with major depressive disorder. In 2003, the first NK1 receptor antagonist, aprepitant (Emend), received marketing approval from the U.S. Food and Drug Administration (FDA). 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「NK1 receptor antagonist」の詳細全文を読む スポンサード リンク
|