Neurokinin agonists

Morris, R., Bleazard, L., Hill, R. G. .The responses of neurons, in the deep dorsal horn of rat spinal cord slices in vitro, to the application of neurokinin agonists are correlated with their responses to peripheral nerve stimulation, J. Physiol. 1992, 452, 252P. 

Neurokinin receptors NK2 receptor agonists (e.g. GR64349) have an anxiogenic profile in animal models while the antagonists (GR100679) have an anti-anxiety effect. However, NKi receptor antagonists have also been reported to have antianxiety activity in the social interaction test (File 1997). 

TRPVl also plays a central role in intercellular pro-inflammatory feedback loops. An important example is mast cells and sensory nerves. Mast cells release tryptase that, in turn, activates the protease-activated receptor PAR-2 activation of PAR-2 then opens TRPVl via PKC [50]. In keeping with this, PAR-2 agonists reduce the heat activation threshold of TRPVl from 42 °C to below body temperature [51]. Excited nerve endings release SP that, as a positive feedback, binds to neurokinin NKl receptors on mast cells. Mast cells also express TRPVl [52]. Consequently, endovanilloids can act in concert to stimulate mast cells and activate capsaicin-sensitive nerve endings. Of relevance is the finding that PAR-2 is up-regulated in the bladder during experimental cystitis [53]. 

Fong, T. M., Huang, R.-R. C., Strader, C. D. Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor, J. Biol. Chem. 1992, 267, 25664-25667. 

Evidences for intermediate conformational states have also been observed in other receptors. Time-resolved peptide-binding studies on the neurokinin receptor revealed that an agonist peptide binds with biphasic... 

Neurokinin receptor ligands - there are two types of NK receptors in the brain. NK2 agonists have been found to be anxiogenic while the antagonists are anxiolytic at least in animal studies. Some NK1 antagonists have also been shown to be anxiolytic in experimental studies. 

MePhe lNKB is a neurokinin B derivative, a TACHYKININ RECEPTOR AGONIST reasonably selective at the NKy-receptor subtype. It is used as a pharmacological tool. 

Sublimaze fentanyl. substance K neurokinin A neuropeptide K. substance P (SP) is a naturally occurring 11 amino acid residue C-terminally amidated peptide, and is a tachykinin present in the brain of vertebrate species, in spinal ganglia and in the intestines. It is formed from the precursor preprotachykinin A (PPT-A). It acts as a tachykinin RECEPTOR AGONIST and Stimulates extravascular smooth muscle, is a powerful VASODILATOR and transient HYPOTENSIVE, and causes salivation and increased capillary permeability. Notably, Af-terminally deleted fragments (e.g. SP(4-11)) are as active as substance P itself on many systems. It is used as a pharmacological tool. 

Substance P (SP) is a naturally occurring neurokinin receptor (NK2) agonist. NK2 is a transmembrane protein receptor of the GPCR-type which regulates brain functions related to depression and anxiety. Substance P is an intensively investigated natural ligand the amino acid sequence of SP is shown in Fig. 4.6. SP has an affinity constant of Ki = 295 nM to its receptor. 

Fig. 4.6 Neurokinin receptor agonist. Substance P is a potent NK receptor agonist. After extensive biological studies, the undecapeptide could be truncated to an active hexapeptide with an improved affinity constant of 11.7 nM. To identify the crucial binding position of the hexapeptide, an alanine scan has been performed. The greatest...

Physical changes in the lung after exposure to aerosolized JP-8 may also underlie the altered systemic effects on lymphoid tissue. Robledo and Witten (1999) reported that treatment of mice with substance P, a neurokinin receptor agonist, protected the lungs from the damaging effects of aerosolized JP-8, including increased permeability, epithelial necrosis, and perivascular edema. Substance P administration was also reported to prevent the loss of spleen and thymus cellularity after JP-8 exposure (250-2,500 mg/m3) and to partially restore the proliferative response of spleen cells to Con A + IL-2 (Harris et al. 1997c). 

Neurokinins (NK), members of the mammalian tachyldnins. They are widely distributed in the central and peripheral nervous systems, and the two neurokinins (NKA and NKB) act as neurotransmitters or neuromodulators. The biological actions on many tissues are mediated via specific G protein-coupled receptors. Among the three subtypes of NK receptors, NKi is the preferred receptor for substance P. Neurokinin A, NKA (also known as substance K, neurokinin a, and neuromedin L), H-His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met -NH2, is the agonist for the NK2 receptor, whereas neurokinin B, NKB (also known as neurokinin and neuromedin K), H-Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met -NH2, mediates its action through the NK3 receptor. Together with substance P, the NK play an important role in pain transmission, neurogenic inflammation, smooth muscle contraction, secretion, vasodilation, and activation of the immune system. The NK were isolated from porcine spinal cord extracts and synthesized by Munekata and coworkers in 1984 [E. Munekata et al., Chem. Lett. 1984, 1013 K. Eolkers et al., Biochem. Biophys. Res. Commun. 1984, 118, 405 J. E. Maggio, Annu. Rev. Neurosci. 1988, 11, 13 Z. Gao,... 

Figure 12.5 Structure-based virtual screening examples for GPCRs. (a) Neurokinin-1 receptor antagonist, IC50 251 nM. (b) alA receptor antagonist, K, 1.4 nM. (c) Two chemokine receptor CCR5 agonists with EC50 values of 3.0 [xM (left) and 1.9 pM (right).

Neurokinin 1 receptor agonists have been found to depolarize (Oh et al. 2000) or hyperpolarize (Jafri and Weinreich 1998) the membrane potential of nodose... 

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