After its discovery in 1931,
substance P (SP) remained the only mammalian member of the family of
tachykinin peptides for several decades.
Tachykinins thus refer to
peptides sharing the common C-terminal amino acid sequence Phe-X-
Gly-Leu-Met x NH2. In recent years the family of mammalian
tachykinins has grown with the isolation of two novel
peptides from bovine and porcine central nervous system (CNS),
neurokinin A and
neurokinin B. In parallel with the identification of multiple endogenous
tachykinins several classes of
tachykinin receptors were discovered. The receptors described so far are named
tachykinin NK1
receptor, tachykinin NK2 receptor and
tachykinin NK1 receptor, respectively. The present review focuses on the pharmacology and putative function of
tachykinin NK1 receptors in brain. The natural
ligand with the highest affinity for the
tachykinin NK1 receptor is SP itself. The C-terminal sequence is essential for activity, the minimum length of a fragment with reasonable affinity for the
tachykinin NK1 receptor is the C-terminal hexapeptide. A rapid advance of knowledge was caused by development of non-peptidic
tachykinin NK1 receptor antagonists. This area is under rapid development and a variety of different chemical classes of compounds are involved. Species-dependent affinities of
tachykinin NK1 receptor antagonists reveal two clusters of compounds, targeting the
tachykinin NK1 receptor subtype found in guinea pig, human or ferret or the one in rat or mouse, respectively. The most recently developed compounds are highly selective, enter the brain and are orally bioavailable. Distinct behavioural effects in experimental animals suggest the involvement of
tachykinin NK1 receptors in nociceptive transmission, basal ganglia function or anxiety and depression. Recent clinical trials in man showed that
tachykinin NK1 receptor antagonists are effective in treating depression and
chemotherapy-induced
emesis. Therefore, it is well possible that
tachykinin NK1 receptor antagonists will be clinically used for treatment of specific CNS disorders within a short period of time.