NK-1 Antagonist 1

[Pharmacological profile of sendide, a tachykinin NK-1 receptor antagonist]

Progress in the characterization of tachykinin receptors and the understanding of the physiological and pathological roles of tachykinins is highly dependent on the discovery of potent and selective antagonists with metabolic stability. We have recently described a peptidic antagonist of the tachykinin NK-1 receptor, sendide (Tyr-D-Phe-Phe-D-His-Leu-Met-NH2), that is a selective and extremely potent antagonist of NK-1 receptors, but displays no antagonistic activity on the response induced by NK-2- or NK-3-receptor agonists in the mouse spinal cord. When co-administered with substance P (SP) intrathecally (i.t.), sendide markedly inhibited the scratching, biting and licking behavior induced by SP in a dose-dependent manner. The antagonistic effect of sendide on the SP-induced behavioral response was approximately 7300 times more potent than that of CP-96,345, a non-peptidic NK-1-receptor antagonist. The duration of the antagonistic effect of sendide was longer than that of CP-96,345. The behavioral response elicited by other NK-1-receptor agonists, septide, physalaemin and [Sar9, Met (O2)11]-SP, was reduced significantly by a small dose of sendide. In the [3H]-SP binding assay using mouse spinal cord membranes, sendide potently displaced [3H]-SP binding, with a potency approximately 5.4 x 10(4) times greater than that of CP-96,345. Moreover, i.t. administration of sendide was found to produce the antinociceptive effect through the blockage of NK-1 receptors in the mouse formalin and capsaicin tests. Sendide is therefore likely to become a powerful pharmacological tool for studying the functional roles of NK-1 receptors in the central nervous system.

NK-1 Antagonists and Itch

Substance P (SP) is an important mediator of pro-inflammatory mechanisms in the skin. It targets multiple cells such as keratinocytes, mast cells, and fibroblasts which are involved in the cutaneous generation of pruritus. This suggests that SP is an interesting target for therapy. In fact, in recent case reports and case series, SP antagonists demonstrated a significant antipruritic effect in acute and chronic pruritus such as drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma, and brachioradial pruritus.

NK-1 Receptor Antagonists and Pruritus: Review of Current Literature

The discovery of the first neurokinin 1 (NK-1) receptor antagonist was a turning point in the prevention of chemotherapy-induced nausea and vomiting. The NK-1 antagonists are a novel class of drugs that possess antidepressant, anxiolytic, and antiemetic properties. Recently, clinicians have also described an anti-itch activity of NK-1 antagonists. We present herein results from currently available data on use of NK-1R antagonists in dermatology. For this purpose, a systemic electronic literature search of the PubMed and CINAHL databases, Cochrane Library, and clinicaltrials.gov website was performed. Based on currently available data, it can be concluded that NK-1 inhibitors show significant antipruritic potential for treatment of chronic pruritus in different dermatological conditions, but further studies are needed to establish the best indications and dosage of these drugs.

Clinical Applications of Substance P (Neurokinin-1 Receptor) Antagonist in Canine Medicine

Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.

The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs

The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less wellknown compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs.