NK1 receptor antagonist
   HOME

TheInfoList



OR:

Neurokinin 1 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 ...
(NK1) antagonists (-pitants) are a novel class of medications that possesses unique
antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
,
anxiolytic An anxiolytic (; also antipanic or antianxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxi ...
, and
antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
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 Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
. An example of a drug in this class is aprepitant. Chemotherapy-induced
emesis Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteriti ...
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 antiemetic effect in both acute and especially in delayed phases of emesis.
Casopitant Casopitant (), former tentative trade names Rezonic (U.S.) and Zunrisa (Europe), is an NK1 receptor antagonist which was undergoing research for the treatment of chemotherapy-induced nausea and vomiting. It was under development by GlaxoSmithK ...
,
netupitant Netupitant is an antiemetic medication. In the United States, the combination drug, combinations of netupitant/palonosetron and the prodrug fosnetupitant/palonosetron (both brand name Akynzeo) are approved by the Food and Drug Administration for ...
and
rolapitant Rolapitant (INN, trade name Varubi in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for ...
are some newer additions in this group. Rolapitant has a significantly longer half-life of 160 hours and was approved by the US FDA in 2015. The first registered clinical use of NK1 receptor antagonists was the treatment of emesis, associated with cancer
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
.


History

In 1931, von Euler and Gaddum discovered substance P (SP) in horse brain and intestine. The substance showed strong
vasodilatory Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
effects and contractile activity on the rabbit gut. A great effort was put into purifying this substance from diverse mammalian tissue, but 30 years of research were without success. Nonmammalian
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
s that elicited the same vasodilatory and contractile effects as SP were discovered by Erspamer in the early 1960s. These
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
s had a common
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
sequence, and were grouped together as
tachykinin 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-termi ...
s. In 1971, Chang managed to purify SP from horse intestine and identify its
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence; SP was then classified as a mammalian
tachykinin 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-termi ...
. Later it became clear that SP was a
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
that was common in the central and peripheral nervous system. In the mid 1980s, the additional mammalian tachykinin neurokinin A (NKA) and neurokinin B (NKB) were discovered. This led to further research, resulting in 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.
Biological research Biology is the scientific study of life. It is a natural science with a broad scope but has several unifying themes that tie it together as a single, coherent field. For instance, all organisms are made up of cells that process hereditary in ...
that identified the many functions of
tachykinin 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-termi ...
s sparked interest in
neurokinin 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-termi ...
receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...
s development. In the 1980s, several
peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...
antagonists derived from SP were the first NK1 receptor antagonists. However, these compounds, like most peptide compounds, had problems with
selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...
,
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...
,
solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...
and
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
. For this reason,
pharmaceutical companies The pharmaceutical industry discovers, develops, produces, and markets drugs or pharmaceutical drugs for use as medications to be administered to patients (or self-administered), with the aim to cure them, vaccinate them, or alleviate symptoms. ...
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 researched extensively and many structures and
patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...
s have appeared. Proposing the concept in the early 1990s, in 1998 Kramer, ''et al.'', reported clinical data on the efficacy and safety of MK-869 (aprepitant) in patients with major depressive disorder. In 2003, the first NK1 receptor antagonist, aprepitant (Emend), received marketing approval from the
U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA).


The neurokinin-1 receptor

Tachykinins are a family of
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
s that share the same
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
region with the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence Phe-X-
Gly Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
- Leu- Met-NH2, where X represents a
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...
residue that is either an
aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...
or a beta-branched
aliphatic In organic chemistry, hydrocarbons ( compounds composed solely of carbon and hydrogen) are divided into two classes: aromatic compounds and aliphatic compounds (; G. ''aleiphar'', fat, oil). Aliphatic compounds can be saturated, like hexane, ...
. The N-terminal region varies between different tachykinins. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles. SP is the most researched and potent member of the tachykinin family. It is an undecapeptide with the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
sequence Arg-
Pro Pro is an abbreviation meaning "professional". Pro, PRO or variants thereof may also refer to: People * Miguel Pro (1891–1927), Mexican priest * Pro Hart (1928–2006), Australian painter * Mlungisi Mdluli (born 1980), South African retired f ...
- Lys-
Pro Pro is an abbreviation meaning "professional". Pro, PRO or variants thereof may also refer to: People * Miguel Pro (1891–1927), Mexican priest * Pro Hart (1928–2006), Australian painter * Mlungisi Mdluli (born 1980), South African retired f ...
- Gln- Gln- Phe- Phe-
Gly Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
- Leu- Met-NH2. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor. Tachykinin NK1 receptor, often referred to as NK1 receptor, is a member of family 1 (
rhodopsin Rhodopsin, also known as visual purple, is a protein encoded by the RHO gene and a G-protein-coupled receptor (GPCR). It is the opsin of the rod cells in the retina and a light-sensitive receptor protein that triggers visual phototransduction ...
-like) of
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
and binds to the Gαq protein. NK1 receptor consists of 407 amino acid residues, and it has a
molecular weight A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bioch ...
of 58.000. NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic
transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequentl ...
(TM) domains with three
extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
and three
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
loops, an
amino-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
and a
cytoplasmic In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...
carboxy-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. The loops have functional sites, including two
cystein Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, someti ...
es amino acids for a
disulfide bridge In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
, Asp- Arg- Tyr, which is responsible for association with
arrestin Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors. Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of ...
and, Lys/ Arg- Lys/ Arg-X-X- Lys/ Arg, which interacts with
G-proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ac ...
.


Drug discovery and development

In 1991, three different groups researched different NK1 receptor antagonists by
screening Screening may refer to: * Screening cultures, a type a medical test that is done to find an infection * Screening (economics), a strategy of combating adverse selection (includes sorting resumes to select employees) * Screening (environmental), a ...
of chemical collections. Eastman Kodak and Sterling Winthrop discovered
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
series of tachykinin NK1 receptor antagonists that yielded some compounds but lacked sufficient
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
for the NK1 receptor, despite structure-activity relationship (SAR) studies that were performed. This series proved to have significant toxicity. Even though many derivatives of the
steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
compounds have been synthesized,
biological activity In pharmacology, biological activity or pharmacological activity describes the beneficial or adverse effects of a drug on living matter. When a drug is a complex chemical mixture, this activity is exerted by the substance's active ingredient or ...
has not been improved.
Rhône-Poulenc Rhône-Poulenc () was a French chemical and pharmaceutical company founded in 1928. In 1999 it merged with Hoechst AG to form Aventis. As of 2015, the pharmaceutical operations of Rhône-Poulenc are part of Sanofi and the chemicals divisions ar ...
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 Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...
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 migraines but then terminated, as was the case with other NK1 receptor antagonists that were tested for the same indication. The third company,
Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
, discovered a benzylamino
quinuclidine Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with p''K''a of the conjugate acid of 11.0.{{cite journal , title=Azatriquinanes: Synthesis, Structure, and Reacti ...
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 Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
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 Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
at this site was performed to produce analogs. The compound CP-99994 was synthesized by replacing the
quinuclidine Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with p''K''a of the conjugate acid of 11.0.{{cite journal , title=Azatriquinanes: Synthesis, Structure, and Reacti ...
ring with a
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
ring and
benzhydryl The benzhydryl compounds are a group of organic compounds whose parent structures include diphenylmethane (which is two benzene rings connected by a single methane), with any number of attached substituents, including bridges. This group typic ...
moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
by a
benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substi ...
group (figure 2). CP-99994 had a high affinity for the human NK1 receptor and it started a great number of structure–activity studies, each intending to identify the structural requirements for high-affinity interaction with the NK1 receptor, and to make the molecule even simpler and improve its chemico-physical and pharmacological properties. CP-99994 eased dental pain in humans and entered phase II clinical trials; these were discontinued because of poor bioavailability. Pfizer researched several other related NK1 receptor antagonists. CJ-11974, also called ezlopitant, was a close analog of CP-96345 that had an isopropyl group on the methoxybenzyl ring. It was developed up to phase II clinical trials for chemotherapy-induced emesis before development was discontinued. CP-122721 was a CP-99994 analog that had a trifluoromethoxy group in the o-methoxybenzyl ring. It entered phase II trials for the treatment of depression, emesis and inflammatory diseases, but no further development has been reported.


Development of the first drug

In 1993,
Merck Merck refers primarily to the German Merck family and three companies founded by the family, including: * the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668 ** Merck Serono (known as EMD Serono in the Unite ...
started performing SAR studies of NK1 receptor antagonists, based on both CP-96345 and CP-99994.
L-733,060 L-733,060 is a drug developed by Merck & Co., Merck which acts as an orally active, non-peptide, selective Receptor antagonist, antagonist for the Tachykinin receptor 1, NK1 Receptor (biochemistry), receptor, binding with a Dissociation constant, ...
is one of the compounds that were developed from CP-99994. It has a 3,5-bistrifluoromethyl benzylether
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
in place of 2-methoxy
benzylamine Benzylamine is an organic chemical compound with the condensed structural formula C6H5CH2NH2 (sometimes abbreviated as PhCH2NH2 or BnNH2). It consists of a benzyl group, C6H5CH2, attached to an amine functional group, NH2. This colorless water- ...
moiety Moiety may refer to: Chemistry * Moiety (chemistry), a part or functional group of a molecule ** Moiety conservation, conservation of a subgroup in a chemical species Anthropology * Moiety (kinship), either of two groups into which a society is ...
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. 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 In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...
on the
phenyl ring In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
were introduced. These changes produced the compound MK-869, which showed high affinity for the NK1 receptor and high oral activity (figure 3). MK-869 is also called aprepitant, and was studied in pain, migraines,
emesis Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteriti ...
and psychiatric disorders. These studies led to the FDA-approved drug
Emend 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 de ...
for chemo therapy-induced nausea and vomiting, and is available for oral use. A water-soluble phosphoryl prodrug for intravenous use, called
fosaprepitant Fosaprepitant (Emend for Injection (US), Ivemend (EU)) is an antiemetic medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent d ...
, is also available and is marketed as Ivemend. Aprepitant was also believed to be effective in the treatment of depression. It entered phase III trials before the development for this indication was discontinued.


Other compounds

Many compounds have been described by various pharmaceutical companies besides the compounds that led to the discovery of aprepitant. GR-205171 (figure 4) was developed by
Glaxo GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...
and was based on CP-99994. GR-205171 had a
tetrazole Tetrazoles are a class of synthetic organic heterocyclic compound, consisting of a 5-member ring of four nitrogen atoms and one carbon atom. The name tetrazole also refers to the parent compound with formula CH2N4, of which three isomers can be fo ...
ring in position 4 of the
benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substi ...
ring of CP-99994 that was intended to increase oral bioavailability and improve pharmacokinetic properties. It was developed up to phase II clinical trials for the treatment of postoperative nausea and vomiting, migraine and motion sickness. It showed good results in
emesis Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteriti ...
, but development was discontinued. LY-303870, or lanepitant (figure 5), is an N-acetylated reduced amide of
L-tryptophan Tryptophan (symbol Trp or W) is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an Alpha_and_beta_carbon , α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with ...
that was discovered by
Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and r ...
. It underwent phase IIa clinical trials for the treatment of osteoarthritis pain but showed no significant effects. Eli Lilly made some SAR work on its structure and developed some compounds that did not enter clinical trials. By a general hypothesis on peptideric
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
binding site, Takeda discovered a series of N-benzylcarboxyamides in 1995. One of those compounds, TAK-637 (figure 6), underwent phase II clinical trials for urinary incontinence, depression and irritable bowel syndrome, but the development was discontinued. There are still other compounds that have been researched in the past and even reached clinical trials, and research continues despite the lack of success in clinical trials.


Binding

There is more than one ligand binding domain on the NK1 receptor for the non-peptide
antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
, and these binding domains 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). Several residues, such as Gln165 (TM4),
His His or HIS may refer to: Computing * Hightech Information System, a Hong Kong graphics card company * Honeywell Information Systems * Hybrid intelligent system * Microsoft Host Integration Server Education * Hangzhou International School, in ...
197 (TM5), His265 (TM6) and Tyr287 (TM7) are involved in the binding of many non-peptide
antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the NK1 receptors. It has been stated that
Ala Ala, ALA, Alaa or Alae may refer to: Places * Ala, Hiiu County, Estonia, a village * Ala, Valga County, Estonia, a village * Ala, Alappuzha, Kerala, India, a village * Ala, Iran, a village in Semnan Province * Ala, Gotland, Sweden * Alad, S ...
-replacement of His197 decreases the binding affinity of CP-96345 for the NK1 receptor. His197 interacts with the
benzhydryl The benzhydryl compounds are a group of organic compounds whose parent structures include diphenylmethane (which is two benzene rings connected by a single methane), with any number of attached substituents, including bridges. This group typic ...
moiety of CP-96345. Experiments have showed that replacing Val116 (TM3) and
Ile Ile may refer to: * iLe, a Puerto Rican singer * Ile District (disambiguation), multiple places * Ilé-Ifẹ̀, an ancient Yoruba city in south-western Nigeria * Interlingue (ISO 639:ile), a planned language * Isoleucine, an amino acid * Anothe ...
290 (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 proven to be meaningful for the binding of several non-peptide antagonists, possibly through the formation of a
hydrogen bond In chemistry, a hydrogen bond (or H-bond) is a primarily electrostatic force of attraction between a hydrogen (H) atom which is covalently bound to a more electronegative "donor" atom or group (Dn), and another electronegative atom bearing a ...
. Phe268 and Tyr287 have been proposed as possible contact points for both agonist and antagonist binding domains. 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. Nonetheless, it has been demonstrated that Ala-replacement of His265 does not affect the binding affinity of CP-96345. Some other residues that are thought to be involved in the binding of non-peptide antagonists to NK1 receptor are
Ser Ser or SER may refer to: Places * Ser, a village in Bogdand Commune, Satu Mare County, Romania * Serpens (Ser), an astronomical constellation of the northern hemisphere * Serres, known as Ser in Serbian, a city in Macedonia, Greece Organization ...
169, Glu193, Lys194, Phe264, Phe267,
Pro Pro is an abbreviation meaning "professional". Pro, PRO or variants thereof may also refer to: People * Miguel Pro (1891–1927), Mexican priest * Pro Hart (1928–2006), Australian painter * Mlungisi Mdluli (born 1980), South African retired f ...
271 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.


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. First, the ion-pair site interactivity with the bridgehead nitrogen; second, the accessory binding site interactivity with the
benzhydryl The benzhydryl compounds are a group of organic compounds whose parent structures include diphenylmethane (which is two benzene rings connected by a single methane), with any number of attached substituents, including bridges. This group typic ...
group; and third, the specific site interactivity with the (2-methoxybenzyl) amino side chain. Studies have shown that compounds with
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
ring have selectivity for NK1 receptor over NK2, NK3,
opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
and 5-HT receptors. By adding an N-heteroaryl-2-phenyl-3-(benzyloxy) group to the
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic compound, heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless ...
, a 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. The bridgehead basic nitrogen is thought to interact with the NK1 receptor by mediating its recognition through ion pair site. It has been found that the basic nitrogen atoms in pyrido ,4-byridine do have an anchoring function in the phospholipid component of the cell membrane. 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 Benzylamine is an organic chemical compound with the condensed structural formula C6H5CH2NH2 (sometimes abbreviated as PhCH2NH2 or BnNH2). It consists of a benzyl group, C6H5CH2, attached to an amine functional group, NH2. This colorless water- ...
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. The presence of an intramolecular face-to-face π–π interaction between two
aromatic rings In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to saturat ...
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 Diazanaphthalenes are a class of aromatic heterocyclic chemical compounds that have the formula C8H6N2. They consist of a naphthalene double ring in which two of the carbon atoms have been replaced with nitrogen atoms. There are ten positional isom ...
ring.


Future development

Chemotherapy-induced
emesis Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteriti ...
is a major problem in cancer treatment. A new compound, T-2328 (figure 7), a non-peptide
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the tachykinin NK1 family, is studied for that purpose. T-2328 is administered intravenously, and treats both acute and delayed emesis. It is proposed to exert its
anti-emetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may b ...
effect through acting on brain NK1 receptors. T-2328 is very potent; the
inhibition constant In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
is of subnanomolar range and is 16 times lower than that of aprepitant. The inhibition is highly selective for NK1 receptors. The NK2 and NK3 receptors are also targets for novel classes of medications, and also show prominent antidepressive and anxiolytic effects. Studies showed that the
inhibition constant In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a m ...
(Ki) for NK2 receptors was >10000-fold higher and for NK3 receptors >1000-fold higher than that for NK1 receptors. The
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Par ...
was also much lower for NK2 and NK3 receptors. Since
tachykinin 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-termi ...
s were discovered, they have been shown to possess biological activity in number of
pathological Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...
and
physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemical ...
systems. Nevertheless, the therapeutic potential of the tachykinin antagonists has not been fully understood.


See also

*
Casopitant Casopitant (), former tentative trade names Rezonic (U.S.) and Zunrisa (Europe), is an NK1 receptor antagonist which was undergoing research for the treatment of chemotherapy-induced nausea and vomiting. It was under development by GlaxoSmithK ...
*
Maropitant Maropitant (INN; trade name: Cerenia ), used as maropitant citrate (USAN), is a neurokinin-1 (NK1) receptor antagonist developed by Zoetis specifically for the treatment of motion sickness and vomiting in dogs. It was approved by the FDA in 200 ...
*
Rolapitant Rolapitant (INN, trade name Varubi in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for ...
*
Tachykinin receptor 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- ...
*
G protein-coupled receptors G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...


References

{{Neurokinin receptor modulators Drug discovery