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. 2019 Sep 1;11(9):443. doi: 10.3390/pharmaceutics11090443

Table 1.

Substance P, its analogues and derivatives: biological activity and potential application in classical medicine.

NK1R ligands Ligand Biological Properties and Applications References
Mammalian NK1R ligands
• Phosphatidylinositol signal pathway activation and intracellular calcium concentration increase; [20]
• Treatment of depression and associated anxiety; [38]
• Prevention of vomiting after anaesthesia or chemotherapy; [39,40]
Substance P (SP, SP(1–11), [Arg1]SP) • Increase of endothelial ion transport and permeability of vessels in tissue inflammation states; [41,42,43,44]
• Neuropathic pain modulation; [45]
• Liver cirrhosis biomarker; [46,47,48]
• Bone tissue metabolism modulator, especially of osteoblast activity at a later stage of bone formation; [47,48]
Arg1-Pro2-Lys3-Pro4-Gln5-Gln6- Phe7-Phe8-Gly9-Leu10-Met11-NH2 • Cancer growth promotor (astrocytoma, melanoma, neuroblastoma, pancreatic cancer), angiogenesis, migration and metastasis; [5,49,50]
(Figure 2) • Study of the synergistic effect of SP and insulin-like growth factor 1 (IGF-1) on corneal epithelial wound healing – synergistic effect possible only in the presence of the SP fragment containing minimum C-terminus 4 amino acids, SP(8–11); [51]
[Thi8,Met(O2)11]SP Pro4-Gln5-Gln6-Phe7-Thi8-Gly9-Leu10-Met(O2)11-NH2 Treatment of recurrent and critically located glioblastoma multiforme; [55]
[Sar9,Met(O2)11]SP(1–11) and (Sendide) [Tyr6,D-Phe7,D-His9]SP(6–11) Studies of the role of NK1R in regulation and release of vasopressin peptide; [56,57]
(X)Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2 (1) or Arg1-Pro2-(X)Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2 (1) Studies of photoactivatable SP derivatives; [59]
Bapa0[(pBzl)PheX]SP (2)
Bapa0[Pro9,(pBzl)Hcy(O2)11]SP (2)
Bapa0[Hcy(ethylaminodansyl)11]SP
Studies of activation of different second messenger pathways as a result of ligand binding to various NK1Rs sites; studies of dual behaviour of the tested SP derivatives: as antagonists at the NK-1M binding site activating AC pathway or agonists at the NK-1m binding site activating PLC pathway; [10]
Septide
[pGlu6,Pro9]SP(6–11)
pGlu6-Phe7-Phe8-Pro9-Leu10-Met11-NH2
Agonist as potent as SP in eliciting smooth muscle contraction, however poor competitor of SP due to interaction with another binding site of NK1R (NK-1m, so-called ‘septide-sensitive’); [7,60]
GR 73,632
NH2(CH2)4C(O)-Phe7-Phe8-Pro9-(Me)Leu10-Met11-NH2
Approximately 200-fold more potent than SP in inducing the characteristic behavioural response in murine models. [61]
Non-mammalian NK1R ligands
Physalaemin Pyr1-Ala2-Asp(OH)3-Pro4-Asp(NH2)5-Lys6-Phe7-Tyr8-Gly9-Leu10-Met11-NH2 Stimulation of extravascular smooth muscles, component of eye drops for Sjögren syndrome treatment and other forms of keratoconjunctivitis sicca; [3,19,62,63]
Eledoisin pGlu1-Pro2-Ser3-Lys4-Asp5-Ala6-Phe7-Ile8-Gly9-Leu10-Met11-NH2 Similar biological activities as Physalaemin but slightly less active and more stable in vivo; clinical trials for limb arteriosclerosis treatment; component of eye drops for Sjögren syndrome; [19,63]
Sialokinin I Asn2-Thr3-Gly4-Asp5-Lys6-Phe7-Tyr8-Gly9-Leu10-Met11-NH2
Sialokinin II, Asp2-Thr3-Gly4-Asp5-Lys6-Phe7-Tyr8-Gly9-Leu10-Met11-NH2
Vasodilation, effect on salivation, influence on the acinar cells of the submandibular glands. [3,64,65]

(1) X = p-benzoylbenzoic moiety; (2) Bapa = biotinyl sulfone-5-aminopentanoic acid; Bzl = benzyl; Hcy = homocysteine; HcyO2 = homocysteine sulfone.