Seite - (000308) - in Biomedical Chemistry: Current Trends and Developments

Substance P 1-7 Binding site Substance P (SP) was the first neuropeptide to be identified (Von Euler, 1931). In the beginning of the 1970s the peptide sequence, H-Arg-Pro- Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, was disclosed (Chang, 1971) and a decade later its belonging to the tachykinin family was affirmed (Erspamer, 1981). Together with neurokinin A (NKA) and neurokinin B (NKB), SP is the most well-known member of this family (Harrison, 2001). Three mammalian tachykinin receptors are known today: the neurokinin (NK) receptors NK1, NK2 and NK3 (Otsuka, 1993). SP is the preferred endogenous ligand for the NK1 receptor, where it acts as a neurotransmitter and a neuromodulator in both the central and peripheral nervous system. In the brain, SP and its corresponding receptor are expressed in areas related to depression (Kramer, 1998), anxiety (De Araujo, 2001) and stress (Culman, 1995; Ebner, 2008) as well as in areas involved in motivation and reward (Hasenohrl, 1991; Huston, 1993). In the spinal cord, SP is expressed in pain processing pathways (Zubrzycka, 2000). 3.3.2.1 SP1-7 and its Binding Site Several of the degradation products of SP have been found to be bioactive, and especially the C-terminal fragments can mimic the effects of the mother peptide. For example, infusion of the C-terminal metabolite SP5–11 into the spinal cord induces nociceptive reactions (Skilling, 1990) and when injected into the dorsal periaqueductal gray matter in rats the C-terminal fragment SP6–11 was shown to produce anxiogenic effects mediated via the NK1 receptor (De Araujo, 2001). The N-terminal fragment SP1–7 is one of the major metabolites of SP. In contrast to the C-terminal metabolites of SP, SP1–7 has been shown to oppose several effects of SP, e.g. the nociceptive effect (Sakurada, 2004), the inflammatory effect (Wiktelius, 2006) and the potentiating effect on opioid withdrawal symptoms (Kreeger, 1993; Zhou, 2003). Interestingly, these effects were not found to be mediated through the NK1 receptor and although the actions of this heptapeptide are well-known, no explicit receptor has yet been identified. However, the potential