The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene. [5]
Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino acid sequence Phe-X-Gly-Leu-Met-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins. [6] [7] [8] The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. [8] Substance P (SP) is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. [6] SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor. [7]
Tachykinin NK1 receptor [9] consists of 407 amino acid residues, and it has a molecular weight of 58,000. [6] [10] NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp-Arg-Tyr, which is responsible for association with arrestin and, Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins. [9] [10] The binding site for substance P and other agonists and antagonists is found between the second and third transmembrane domains. The NK-1 receptor is found on human chromosome 2 and is located on the cell's surface as a cytoplasmic receptor. [11]
The NK1 receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells. [9] [12] [8] [10] The binding of SP to the NK1 receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation. [13] NK1 receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression. [14] Other diseases in which the NK1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders. [15]
SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. [6] When NK1 receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the arachidonic acid mobilization via phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase. [16] It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, it is known to sensitize neutrophils and enhance dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine and GABA. It is also known to secrete catecholamines and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E2 and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output. [8]
In combination therapy, NK1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK1 receptor antagonists. NK1 receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT3 antagonist treatments. [15] It has been reported that centrally-acting NK1 receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms. [12]
This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants. [17] [18] It is also a potential treatment for alcoholism and opioid addiction. [19] In addition, it has been identified as a candidate in the etiology of bipolar disorder. [20] Finally NK1R antagonists may also have a role as novel antiemetics [21] and hypnotics. [22] [23]
Many selective ligands for NK1 are now available, several of which have gone into clinical use as antiemetics.
Substance P (SP) is an undecapeptide and a type of neuropeptide, belonging to the tachykinin family of neuropeptides. It acts as a neurotransmitter and a neuromodulator. Substance P and the closely related neurokinin A (NKA) are produced from a polyprotein precursor after alternative splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
Aprepitant, sold under the brand name Emend among others, is a medication used to prevent chemotherapy-induced nausea and vomiting (CINV) and to prevent postoperative nausea and vomiting (PONV). It may be used together with ondansetron and dexamethasone. It is taken by mouth or administered by intravenous injection.
Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an Aromatic or an Aliphatic amino acid. The genes that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptides by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.
Physalaemin is a tachykinin peptide obtained from the Physalaemus frog, closely related to substance P. Its structure was first elucidated in 1964.
There are three known mammalian tachykinin receptors termed NK1, NK2 and NK3. All are members of the 7 transmembrane G-protein coupled receptor family and induce the activation of phospholipase C, producing inositol triphosphate (so called Gq-coupled).
Kassinin is a peptide derived from the Kassina frog. It belongs to tachykinin family of neuropeptides. It is secreted as a defense response, and is involved in neuropeptide signalling.
Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.
Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.
Substance-K receptor is a protein that in humans is encoded by the TACR2 gene.
Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the TACR3 gene.
Tachykinin-3 is a protein that in humans is encoded by the TAC3 gene.
Osanetant (developmental code name SR-142,801) is a neurokinin 3 receptor antagonist which was developed by Sanofi-Synthélabo and was being researched for the treatment of schizophrenia but was discontinued. It was the first non-peptide NK3 antagonist developed in the mid-1990s.
L-733,060 is a drug developed by Merck which acts as an orally active, non-peptide, selective antagonist for the NK1 receptor, binding with a Ki of 0.08 nM. Only one enantiomer is active which has made it the subject of several asymmetric synthesis efforts.
Vestipitant (INN) is a drug developed by GlaxoSmithKline which acts as a selective antagonist for the NK1 receptor. It is under development as a potential antiemetic and anxiolytic drug, and as a treatment for tinnitus and insomnia.
Ezlopitant (INN, code name CJ-11,974) is an NK1 receptor antagonist. It has antiemetic and antinociceptive effects. Pfizer was developing ezlopitant for the treatment of irritable bowel syndrome but it appears to have been discontinued.
The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.
Netupitant is an antiemetic medication. In the United States, the combinations of netupitant/palonosetron and the prodrug fosnetupitant/palonosetron are approved by the Food and Drug Administration for the prevention of acute and delayed chemotherapy-induced nausea and vomiting, including highly emetogenic chemotherapy such as with cisplatin. In the European Union, the combinations are approved by the European Medicines Agency (EMA) for the same indication.
Vofopitant (GR205171) is a drug which acts as an NK1 receptor antagonist. It has antiemetic effects as with other NK1 antagonists, and also shows anxiolytic actions in animals. It was studied for applications such as the treatment of social phobia and post-traumatic stress disorder, but did not prove sufficiently effective to be marketed.
Lanepitant (INN, code name LY303870), developed by Eli Lilly, is a drug which acts as a selective antagonist of the NK1 receptor, and was one of the first compounds developed that act at this target. It was under development as a potential analgesic drug, but despite promising results in initial animal studies, human clinical trials against migraine, arthritis and diabetic neuropathy all failed to show sufficient efficacy to support further development, with the drug being only marginally more effective than placebo and inferior to older comparison drugs such as naproxen. Failure of analgesic action was thought to be due to poor penetration of the blood–brain barrier in humans, but research has continued into potential applications in the treatment of other disorders with a peripheral site of action, such as corneal neovascularization.
Burapitant (SSR-240,600) is a drug developed by Sanofi-Aventis which was one of the first compounds developed that acts as a potent and selective antagonist for the NK1 receptor. While burapitant itself did not proceed beyond early clinical trials and was never developed for clinical use in humans, promising animal results from this and related compounds have led to a number of novel drugs from this class that have now been introduced into medical use.
