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The discovery of neurokinin 1 (NK₁) receptor antagonist was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.^[1] Chemotherapy-induced emesis appears to consist of acute and delayed phases. So far the acute phase emesis responds to 5-HT3 antagonists while the delayed phase remains difficult to control. The discovery and development of NK1 receptor antagonists have elicited anti-emetic effect in both acute and especially in delayed phases of emesis.^[2]

The first registered clinical use of NK₁ receptor antagonists was the treatment of emesis, associated with cancer chemotherapy. ^[3]

History

In 1931, von Euler and Gaddum discovered Substance P (SP) in horse brain and intestine. The substance showed strong vasodilatory effects and contractile activity on the rabbit gut. A great effort was put in to purifying this substance from diverse mammalian tissue, but without success for over 30 years. Nonmammalian peptides, that elicited the same vasodilatory and contractile effects as SP, were discovered by Erspamer in the early 60's. These peptides had a common C-terminal sequence ( Phe-Xaa- Gly-Leu- MetNH₂) and were grouped together as tachykinins. In 1971 Chang managed to purify SP from horse intestine and identify its aminoacid sequence and as a result SP was classified as a mammalian tachykinin. In the 70's it became clear that SP was a neuropeptide that was common in the central and peripheral nervous system. In the mid 80's, the additional mammalian tachykinin [[Neurokinin A | neurokinin A (NKA)] and neurokinin B (NKB) were discovered.^[4]^[5] This led to further research, resulting with the isolation of the genes that encoded the mammalian tachykinins and eventually the discovery of three different tachykinin receptors. In 1984 it was decided that the tachykinin receptors should be called tachykinin NK₁ receptor, tachykinin NK₂ receptor and tachykinin NK₃ receptor.^[4]^[6] Many biological researches on the function of tachykinins revealed its numerous functions and interest in neurokinin receptor antagonists development arose.^[5] In the 80’s, several peptide antagonists derived from SP were the first NK₁ receptor antagonists. However, these compounds had the same problems most peptide compounds have, related to selectivity, potency, solubility and bioavailability. For that reason pharmaceutical companies concentrated on developing non-peptide NK₁ receptor antagonists and in 1991 three different companies revealed their first results. Since then, non-peptide NK₁ receptor antagonists have been extensively researched and many structures and patents have appeared. In 2003 the first NK₁ receptor antagonist, aprepitant ( Emend^®), received marketing approval from the FDA.^[7]^[8]^[9]

The neurokinin-1 receptor

Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the aminoacid 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.^[10]^[11]^[12] The term tachykinin originates in the rapid onset of action the peptides cause in smooth muscles.^[12] SP is the most researched and potent member of the tachykinin family. It is an undecapeptide with the aminoacid sequence Arg- Pro- Lys- Pro- Gln- Gln- Phe- Phe-[[Glycine | Gly]- Leu- Met-NH₂.^[10] SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK₁ receptor.^[11] Tachykinin NK₁ receptor, often referred to as NK₁ receptor, is a member of family 1 (rhodopsin-like) of G protein-coupled receptors.^[5] NK1 receptor consists of 407 aminoacid residues and it has a molecular weight of 58.000.^[10]^[13] NK₁ receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, amino-terminus and a cytoplasmic carboxy-terminus. The loops have a couple of functional sites, including two cysteines for a disulfide bridge, Asp- Arg- Tyr, that is responsible for association with arrestin and Lys/Arg- Lys/ Arg-X-X- Lys/ Arg that interacts with G-proteins.^[5]^[13]

Distribution and function

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.^[5]^[6]^[12]^[13] The binding of SP to the NK₁ receptor has been associated with the transmission of stress signals and pain, contraction of smooth muscles and inflammation.^[14] NK₁ receptor antagonists have also been studied in migraine, emesis and psychiatric disorder. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression.^[9] Other diseases that the NK₁ receptor system is involved in, include asthma, rheumatoid arthritis and gastrointestinal disorder.^[8]

Mechanism

SP is synthesized by neurons and transported to synaptic vesicles and the release of SP is by calcium-dependent mechanisms which has a depolarizing action.^[10] 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.^[15] It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, 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 increase in corticosteroid output.^[12] 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 establiched [[5-HT₃ antagonist]] treatments.^[8] 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.^[6]

Drug discovery and development

In 1991, three different research groups were researching different NK₁ receptor antagonists by screening of chemical collections. Eastman Kodak discovered steroid series of tachykinin NK₁ receptor antagonists that gave a couple of compounds but didn’t have sufficient affinity for the NK1 receptor, despite structure-activity relationship (SAR) studies that were performed. This series proved to have significant toxicity. Even though many derivates of the steroid compounds have been synthesized, biological activity hasn’t been improved.^[9]^[15]

Rhone-Poulnec discovered the compound RP-67580 which has high affinity for the NK₁ receptor in rats and mice but not in humans. SAR studies, that were performed in order to improve the selectivity for the human NK₁ receptor, resulted in the development of a compound called RPR-100893. This compound showed good activity in vivo and in models of pain and was developed up to phase II for the treatment of migraine but then terminated, as has happened to other NK₁ receptor antagonists that have been tested for the same indication.^[9]^[15]

The third company, Pfizer, discovered a benzylamino quinuclidine structure, which was called CP-96345 (figure 1). CP-96345 has a rather simple structure, composed of a rigid quinuclidine scaffold containing a basic nitrogen atom, a benzhydril moiety and an o-methoxy-benzylamine group. This compound showed high affinity for the NK₁ receptor, but it also interacted with Ca²⁺ binding sites. Strongly basic quinuclidine nitrogen on the compound was considered to be responsible for this Ca²⁺ binding, which caused a number of systemic effects, unrelated to the blocking of the NK₁ receptor. For that reason and also to simplify the structure, alkylation at this site was performed to produce analogs.

The compound CP-99994 was synthesized by replacing the quinuclidine ring with a piperidine ring and benzhydryl moiety by a benzyl group (figure 2).^[9]^[15] CP 99994 had a high affinity for the human NK1 receptor and it started a great amount of structure-activity studies, with the purpose to identify the structural requirements for high affinity interaction with the NK₁ receptor, as well as making the molecule even simpler and improve its chemico-physical and pharmacological properties.^[15] CP-99994 eased dental pain in humans and made it to phase II clinical trials, that were discontinued because of poor bioavailability. Pfizer researched several other related NK₁ receptor antagonists, and one of them, CP-122721, also made it to phase II clinical trials for treatment of depression, emesis and inflammatory diseases before development was terminated.^[9]

Development of the first drug

In 1993 Merck started performing SAR studies of NK₁ receptor antagonists, based on both CP-96345 and CP-99994. L-733060 is one of the compounds that were developed from CP-99994. It has a 3,5-bistrifluoromethyl benzylether piperidine in place of 2-methoxy benzylamine moiety of CP-99994 compound. To improve oral bioavailability the piperidine nitrogen was functionalized in order to reduce its basic nature. The group that gave the best effects on basicity was 3-oxo-1,2,4-triazol-5-yl moiety and it gave compounds such as L-741671 and L-742694. A morpholine nucleus that was introduced in L-742694 was found to enhance NK₁ binding affinity.^[8] This nucleus was preserved in further modifications. In order to prevent possible metabolic deactivation several refinements such as methylation on the C alfa of the benzyl ring and fluorination on the phenyl ring were introduced. These changes produced the compound MK-869, which showed high affinity for the NK₁ receptor and high oral activity. The progress is illustrated in figure 3. MK-869 is also called aprepitant and was studied in pain, migraine, emesis and psychiatric disorder. Those studies led to the FDA approved drug Emend^®, which is indicated for emesis. Emend^® is both available as oral and intravenous pharmaceutical forms.^[9]

Binding

There is more than one ligand binding domain on the NK₁ receptor for the non-peptide antagonists and they can be found in various places. The main ligand binding site is in the hydrophobic core between the loops and the outer segments of transmembrane domains 3 – 7 (TM3 - TM7).^[13] Several residues, such as Gln165 (TM4), His197 (TM5), His265 (TM6) and Tyr287 (TM7) are involved in the binding of many non-peptide antagonists of the NK₁ receptors.^[4]^[13] It has been stated that Ala-replacement of His197 decreases the binding affinity of CP-96345 for the NK₁ receptor. His197 interacts with the benzhydryl moiety of CP-96345. Experiments have showed that replacing Val116 (TM3) and Ile290 (TM7) decreases the binding affinity of CP-96345. Evidence indicates that these residues probably do not interact with antagonists, but would rather indirectly influence the overall conformation of the antagonist binding site. The residue Gln165 (TM4) has also showed to be meaningful for the binding of several non-peptide antagonists, possibly through the formation of a hydrogen bond.^[15]^[16] Phe268 and Tyr287 have been proposed as possible contact points for both agonist and antagonist binding domains.^[13]

The significance of His265 has been confirmed in the binding of antagonists to NK₁ receptor. His265 interacts favorably with the 3,5-bis-trifluoromethylphenyl group (TFMP group) of an analog CP-96345. Despite this it has been demonstrated that Ala-replacement of His265 does not affect the binding affinity of CP-96345. ^[8]

Some other residues which are thought to be involved in the binding of non-peptide antagonists to NK₁ receptor are Ser169, Glu193, Lys194, Phe264, Phe267, Pro271 and Tyr272. Each structural class of non-peptide NK₁ receptor antagonists appears to interact with a specific set of residues within the common binding pocket.^[4]^[13]

Structure-activity relationship (SAR) and pharmacophore

There are at least three essential elements which are important for the interactivity of a ligand with the NK₁ receptor. Firstly the ion-pair site interactivity with the bridgehead nitrogen, secondly the accessory binding site interactivity with the benzhydryl group and thirdly the specific site interactivity with the (2-methoxybenzyl) amino side chain. Studies have shown that compounds with piperidine ring have selectivity for NK₁ receptor over NK₂, NK₃, opioid and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the piperidine, selective NK₁ receptor antagonist is produced. Studies have also shown that the dihedral angle between groups on C-2 and C-3 in CP-99994 is critical for activity of the NK₁ receptor antagonists.^[12] The bridgehead basic nitrogen is thought to interact with the NK₁ receptor by mediating its recognition through ion pair site.^[14] It has been found that the basic nitrogen atoms in pyrido[3,4-b]pyridine do have an anchoring function in the phospholipid component of the cell membrane.^[12]

In the development of MK-869 it was discovered that 3,5-disubstitution of the benzyl ring in the ether series gave greater potency than the 2-methoxy substitution in earlier benzylamine structures. It also was revealed that the TFMP group appeared to be especially important and it is believed that it enhances activity in vivo and improves metabolism. Other groups, like the ortho-methoxyphenyl group, can be important in specific cases, but are thought to play a greater role in ligand preorganization through intramolecular hydrogen bonding, rather than through direct interaction with binding site residue.^[8] The presence of an intramolecular face-to-face π-π interaction between two aromatic rings is a common feature of high affinity NK₁ receptor antagonists. This feature is thought to be important in stabilizing the bioactive conformation. This interaction can be increased with a conformationally restricted system, such as an eight- membered ring introduced into the naphthyridine ring.^[14]

Future development

Chemotherapy-induced emesis is a major problem in cancer treatment. A new compound, T-2328, a non-peptide antagonist of the tachykinin NK₁ family is presently studied for that purpose. T-2328 is administered intravenously and treats both acute and delayed emesis. It is proposed to exert its anti-emetic effect through acting on brain NK₁ receptors. T-2328 is very potent, the inhibition constant is of subnanomolar range and is 16 times lower than that of aprepitant. The inhibition is highly selective for NK₁ receptors. Studies showed that the [[enzyme inhibitor | inhibition constant] (Ki) for NK₂ receptors was >10000-fold higher and for NK₃ receptors >1000-fold higher, than that for NK₁ receptors. The affinity was also much lower for NK₂ and NK₃ receptors.^[2] This will hopefully lead to a new drug on the market. This subject is widely under investigation and the need for new drugs is significant. Since tachykinins were discovered they have been shown to possess biological activity in number of pathological and physiological systems. Nevertheless the therapeutic potential of the tachykinin antagonists have not been fully understood.^[3]

References

^ Hesketh, P. J. (1994), "New treatment options for chemotherapy-induced nausea and vomiting", Supportive care in cancer, 12 (8): 550–554
^ ^a ^b Watanabe, Y.; Asai, H.; Ishii, T.; Kiuchi, S.; Okamoto, M.; Taniguchi, H.; Nagasaki, M.; Saito, A. (Januar 2008), "Pharmacological characterization of T-2328, 2-fluoro-4 '-methoxy-3 '-((((2S,3S)-2-phenyl-3-piperidinyl)amino)methyll)(1,1 '-biphenyl)-4-carbonitrile dihydrochloride, as a brain-penetrating antagonist of tachykinin NK1 receptor", Journal of pharmacological sciences, 106 (1): 121–127 {{citation}}: Check date values in: |date= and |year= / |date= mismatch (help)
^ ^a ^b Brain, S. D.; Cox, H. M. (2006), "Neuropeptides and their receptors: innovative science providing novel therapeutic targets", British journal of pharmacology, 147: S202–S211
^ ^a ^b ^c ^d Maggi, C. A. (September 1994), "Mammalian Tachykinin Receptors", General Pharmacology, 26 (5): 911–944{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e Satake, H.; Kawada, T. (August 2006), "Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors", Current Drug Targets, 7 (8): 963–974{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c Saria, A. (June 1999), "The Tachykinin NK₁ receptor in the brain: pharmacology and putative functions", European Journal of Pharmacology, 375 (1–3): 51–60{{citation}}: CS1 maint: date and year (link)
^ Hoffman, T.; Bös, M.; Stadler, H.; Schnider, P.; Hunkeler, W.; Godel, T.; Galley, G.; Ballard, T. M.; Higgins, G. A.; Poli, S. M.; Sleight, A. J. (March 2006), "Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists", Bioorganic & Medicinal Chemistry Letters, 16 (5): 1362=1365{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e ^f Humphrey, J. M. (2003), "Medicinal Chemistry of Selective Neurokinin-1 Antagonists", Current Topics in Medicinal Chemistry, 3 (12): 1423–1435{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e ^f ^g Quartara, L.; Altamura, M. (August 2006), "Tachykinin receptors antagonists: From research to clinic", Current drug targets, 7 (8): 975–992{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d Ho, W. Z.; Douglas, S. D. (December 2004), "Substance P and neurokinin-1 receptor modulation of HIV", Journal of Neuroimmunology, 157 (1–2): 48–55{{citation}}: CS1 maint: date and year (link)
^ ^a ^b Page, N. M. (August 2005), "New challenges in the study of the mammalian Tachykinins", Peptides, 26 (8): 1356–1368{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e ^f Datar, P.; Srivastava, S.; Coutinho, E.; Govil, G. (2004), "Substance P: Structure, Function, and Therapeutics", Current Topics in Medicinal Chemistry, 4 (1): 75–103{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e ^f ^g Almeida, T. A.; Rojo, J.; Nieto, P. M.; Hernandez first4 = M.; Martin, J. D.; Candenas, M. L. (August 2004), "Tachykinins and Tachykinins Receptors: Structure and Activity Relationships", Current Medicinal Chemistry, 11 (15): 2045–2081 {{citation}}: Missing pipe in: |last4= (help)CS1 maint: date and year (link) CS1 maint: numeric names: authors list (link)
^ ^a ^b ^c Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. (March 2005), "Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK₁ antagonists", Bioorganic and Medicinal Chemistry Letters, 15 (5): 1479–1484{{citation}}: CS1 maint: date and year (link)
^ ^a ^b ^c ^d ^e ^f Quartara, L.; Maggi, C. A. (December 1997), "The tachykinin NK₁ receptor. Part I: Ligands and mechanisms of cellular activation", Neuropeptides, 31 (6): 537–563{{citation}}: CS1 maint: date and year (link)
^ Pennefather, J. N.; Lecci, A.; Candenas, M. L.; Patak, E.; Pinto, F. M.; Maggi, C. A. (2004), "Tachykinins and tachykinin receptors: a growing family", Life Sciences, 74 (12): 1445–1463

[Hesketh_2004-1] Hesketh, P. J. (1994), "New treatment options for chemotherapy-induced nausea and vomiting", Supportive care in cancer, 12 (8): 550–554

[Watanabe_2008-2] Watanabe, Y.; Asai, H.; Ishii, T.; Kiuchi, S.; Okamoto, M.; Taniguchi, H.; Nagasaki, M.; Saito, A. (Januar 2008), "Pharmacological characterization of T-2328, 2-fluoro-4 '-methoxy-3 '-((((2S,3S)-2-phenyl-3-piperidinyl)amino)methyll)(1,1 '-biphenyl)-4-carbonitrile dihydrochloride, as a brain-penetrating antagonist of tachykinin NK1 receptor", Journal of pharmacological sciences, 106 (1): 121–127 {{citation}}: Check date values in: |date= and |year= / |date= mismatch (help)

[Brain_2006-3] Brain, S. D.; Cox, H. M. (2006), "Neuropeptides and their receptors: innovative science providing novel therapeutic targets", British journal of pharmacology, 147: S202–S211

[Maggi_1994-4] Maggi, C. A. (September 1994), "Mammalian Tachykinin Receptors", General Pharmacology, 26 (5): 911–944{{citation}}: CS1 maint: date and year (link)

[Satake_2006-5] Satake, H.; Kawada, T. (August 2006), "Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors", Current Drug Targets, 7 (8): 963–974{{citation}}: CS1 maint: date and year (link)

[Saria_1999-6] Saria, A. (June 1999), "The Tachykinin NK₁ receptor in the brain: pharmacology and putative functions", European Journal of Pharmacology, 375 (1–3): 51–60{{citation}}: CS1 maint: date and year (link)

[Hoffman_2006-7] Hoffman, T.; Bös, M.; Stadler, H.; Schnider, P.; Hunkeler, W.; Godel, T.; Galley, G.; Ballard, T. M.; Higgins, G. A.; Poli, S. M.; Sleight, A. J. (March 2006), "Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists", Bioorganic & Medicinal Chemistry Letters, 16 (5): 1362=1365{{citation}}: CS1 maint: date and year (link)

[Humphrey_2003-8] ^ ^a ^b ^c ^d ^e ^f Humphrey, J. M. (2003), "Medicinal Chemistry of Selective Neurokinin-1 Antagonists", Current Topics in Medicinal Chemistry, 3 (12): 1423–1435{{citation}}: CS1 maint: date and year (link)

[Quartara_2006-9] ^ ^a ^b ^c ^d ^e ^f ^g Quartara, L.; Altamura, M. (August 2006), "Tachykinin receptors antagonists: From research to clinic", Current drug targets, 7 (8): 975–992{{citation}}: CS1 maint: date and year (link)

[Ho_2004-10] Ho, W. Z.; Douglas, S. D. (December 2004), "Substance P and neurokinin-1 receptor modulation of HIV", Journal of Neuroimmunology, 157 (1–2): 48–55{{citation}}: CS1 maint: date and year (link)

[Page_2005-11] Page, N. M. (August 2005), "New challenges in the study of the mammalian Tachykinins", Peptides, 26 (8): 1356–1368{{citation}}: CS1 maint: date and year (link)

[Datar_2004-12] ^ ^a ^b ^c ^d ^e ^f Datar, P.; Srivastava, S.; Coutinho, E.; Govil, G. (2004), "Substance P: Structure, Function, and Therapeutics", Current Topics in Medicinal Chemistry, 4 (1): 75–103{{citation}}: CS1 maint: date and year (link)

[Almeida_2004-13] ^ ^a ^b ^c ^d ^e ^f ^g Almeida, T. A.; Rojo, J.; Nieto, P. M.; Hernandez first4 = M.; Martin, J. D.; Candenas, M. L. (August 2004), "Tachykinins and Tachykinins Receptors: Structure and Activity Relationships", Current Medicinal Chemistry, 11 (15): 2045–2081 {{citation}}: Missing pipe in: |last4= (help)CS1 maint: date and year (link) CS1 maint: numeric names: authors list (link)

[Seto_2005-14] Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. (March 2005), "Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,3-b]- and [2,3-b]-1,5-oxazocin-6-ones as NK₁ antagonists", Bioorganic and Medicinal Chemistry Letters, 15 (5): 1479–1484{{citation}}: CS1 maint: date and year (link)

[Quartara_1997-15] ^ ^a ^b ^c ^d ^e ^f Quartara, L.; Maggi, C. A. (December 1997), "The tachykinin NK₁ receptor. Part I: Ligands and mechanisms of cellular activation", Neuropeptides, 31 (6): 537–563{{citation}}: CS1 maint: date and year (link)

[Pennefather_2004-16] Pennefather, J. N.; Lecci, A.; Candenas, M. L.; Patak, E.; Pinto, F. M.; Maggi, C. A. (2004), "Tachykinins and tachykinin receptors: a growing family", Life Sciences, 74 (12): 1445–1463

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 == The neurokinin-1 receptor ==
-[[Tachykinin | Tachykinins]] are a family of [[Neuropeptide | neuropeptides]] that share the same [[Hydrophobe | hydrophobic]] [[C-terminal]] region with the [[aminoacid]] [[Peptide | sequence]] [[Phenylalanine | Phe]]-X-[[Glycine | Gly]]-[[Leucine | Leu]]-[[Methionine | Met]]-NH<sub>2</sub>, where X represents a [[hydrophobic]] residue that is either an [[aromatic]] or a beta-branched [[aliphatic]]. The [[N-terminal]] region varies between different [[Tachykinin | tachykinins]].<ref name = Ho_2004>{{Citation | last = Ho | first = W. Z. | last2 = Douglas | first2 = S. D. | title = Substance P and neurokinin-1 receptor modulation of HIV | journal = Journal of Neuroimmunology | volume = 157 | issue = 1-2 | pages = 48-55 | date = December 2004 | year = 2004 |url= http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03-4DP8JT6-2&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=5915660&md5=3e140fa2944d54a39f08db8451ff9005=Citation}}</ref><ref name = Page_2005>{{Citation | last = Page | first = N. M. | title = New challenges in the study of the mammalian Tachykinins | journal = Peptides | volume = 26 | issue = 8 | pages = 1356 - 1368 | date = August 2005 | year = 2005 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0M-4G0DDS8-4&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000068853&_version=1&_urlVersion=0&_userid=5915660&md5=9523f37237e3a7147329fb4f28ffacec=Citation}}</ref><ref name = Datar_2004>{{Citation | last = Datar | first = P. | last2 = Srivastava | first2 = S. | last3 = Coutinho | first3 = E. | last4 = Govil | first4 = G. | title = Substance P: Structure, Function, and Therapeutics | journal = Current Topics in Medicinal Chemistry | volume = 4 | issue = 1 | pages = 75-103 | date = 2004 | year = 2004 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=14&sid=cbd0171a-72ef-47c3-bae2-063f39b1af3a%40sessionmgr2&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=12076762=Citation}}</ref> The term [[tachykinin]] originates in the rapid onset of action the [[Peptide | peptides]] cause in [[Smooth muscle | smooth muscles]].<ref name="Datar_2004"/> [[Substance P | SP]] is the most researched and potent member of the [[tachykinin]] family. It is an undecapeptide with the [[aminoacid]] sequence [[Arginine | Arg]]-[[Proline | Pro]]-[[Lysine | Lys]]-[[proline | Pro]]-[[Glutamine | Gln]]-[[Glutamine | Gln]]-[[Phenylalanine | Phe]]-[[Phenylalanine | Phe]]-[[Glycine | Gly]-[[Leucine | Leu]]-[[Methionine | Met]]-NH<sub>2</sub>.<ref name="Ho_2004"/> [[Substance P | SP]] binds to all three of the [[tachykinin]] receptors, but it binds most strongly to the NK<sub>1</sub> receptor.<ref name="Page_2005"/>
+[[Tachykinin | Tachykinins]] are a family of [[Neuropeptide | neuropeptides]] that share the same [[Hydrophobe | hydrophobic]] [[C-terminal]] region with the [[aminoacid]] [[Peptide | sequence]] [[Phenylalanine | Phe]]-X-[[Glycine | Gly]]-[[Leucine | Leu]]-[[Methionine | Met]]-NH<sub>2</sub>, where X represents a [[hydrophobic]] residue that is either an [[aromatic]] or a beta-branched [[aliphatic]]. The [[N-terminal]] region varies between different [[Tachykinin | tachykinins]].<ref name = Ho_2004>{{Citation | last = Ho | first = W. Z. | last2 = Douglas | first2 = S. D. | title = Substance P and neurokinin-1 receptor modulation of HIV | journal = Journal of Neuroimmunology | volume = 157 | issue = 1-2 | pages = 48-55 | date = December 2004 | year = 2004 |url= http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03-4DP8JT6-2&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=5915660&md5=3e140fa2944d54a39f08db8451ff9005=Citation}}</ref><ref name = Page_2005>{{Citation | last = Page | first = N. M. | title = New challenges in the study of the mammalian Tachykinins | journal = Peptides | volume = 26 | issue = 8 | pages = 1356 - 1368 | date = August 2005 | year = 2005 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0M-4G0DDS8-4&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000068853&_version=1&_urlVersion=0&_userid=5915660&md5=9523f37237e3a7147329fb4f28ffacec=Citation}}</ref><ref name = Datar_2004>{{Citation | last = Datar | first = P. | last2 = Srivastava | first2 = S. | last3 = Coutinho | first3 = E. | last4 = Govil | first4 = G. | title = Substance P: Structure, Function, and Therapeutics | journal = Current Topics in Medicinal Chemistry | volume = 4 | issue = 1 | pages = 75-103 | date = 2004 | year = 2004 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=14&sid=cbd0171a-72ef-47c3-bae2-063f39b1af3a%40sessionmgr2&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=12076762=Citation}}</ref> The term [[tachykinin]] originates in the rapid onset of action the [[Peptide | peptides]] cause in [[Smooth muscle | smooth muscles]].<ref name="Datar_2004"/> [[Substance P | SP]] is the most researched and potent member of the [[tachykinin]] family. It is an undecapeptide with the [[aminoacid]] sequence [[Arginine | Arg]]-[[proline | Pro]]-[[Lysine | Lys]]-[[proline | Pro]]-[[Glutamine | Gln]]-[[Glutamine | Gln]]-[[Phenylalanine | Phe]]-[[Phenylalanine | Phe]]-[[Glycine | Gly]-[[Leucine | Leu]]-[[Methionine | Met]]-NH<sub>2</sub>.<ref name="Ho_2004"/> [[Substance P | SP]] binds to all three of the [[tachykinin]] receptors, but it binds most strongly to the NK<sub>1</sub> receptor.<ref name="Page_2005"/>
 Tachykinin NK<sub>1</sub> receptor, often referred to as NK<sub>1</sub> receptor, is a member of family 1 ([[rhodopsin]]-like) of [[G protein-coupled receptors]].<ref name="Satake_2006"/> NK1 receptor consists of 407 [[Amino acid | aminoacid]] residues and it has a [[molecular weight]] of 58.000.<ref name ="Ho_2004"/><ref name = Almeida_2004>{{Citation | last = Almeida | first = T. A. | last2 = Rojo | first2 = J. | last3 = Nieto | first3 = P. M. | last4 = Hernandez  first4 = M. | last5 = Martin | first5 = J. D. | last6 = Candenas | first6 = M. L. | title = Tachykinins and Tachykinins Receptors: Structure and Activity Relationships | journal = Current Medicinal Chemistry | volume = 11 | issue = 15 | pages = 2045-2081 | date = August 2004 | year = 2004 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=4&sid=4b46c517-3764-45fc-9dbd-1cb9d1cec680%40sessionmgr3&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=13996759=Citation}}</ref> NK<sub>1</sub> receptor, as well as the other [[tachykinin]] receptors, is made of seven [[hydrophobic]] [[transmembrane]] (TM) [[domains]] with three [[extracellular]] and three [[intracellular]] loops, [[amino-terminus]] and a [[cytoplasmic]] [[carboxy-terminus]]. The loops have a couple of functional sites, including two [[Cystein | cysteines]] for a [[disulfide bridge]], [[Aspartic acid | Asp]]-[[Arginine | Arg]]-[[Tyrosine | Tyr]], that is responsible for association with [[arrestin]] and [[Lysine | Lys]]/[[Arginine |Arg]]-[[Lysine | Lys]]/[[Arginine | Arg]]-X-X-[[Lysine | Lys]]/[[Arginine | Arg]] that interacts with [[G-proteins]].<ref name="Satake_2006"/><ref name="Almeida_2004"/>