Tachykinin Receptors

The tachykinins represent a large family of peptides whose common structural feature is the C-terminal amino acid sequence Phe-X-Gly-Leu-Met-NH2. Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), hemokinin-1, endokinin A and endokinin B are the major tachykinins found in mammals. They are encoded by three genes named TAC1, TAC3 and TAC4 by the Human Genome Organization Nomenclature Committee, whereas the gene for chromosome 14 tachykinin-like peptide-1 awaits to be identified. SP and NKA are derived from the TAC1 (preprotachykinin-A or PPT-A) gene. Alternative splicing of the TAC1 transcript generates four different precursor proteins (α-, β-, γ- and δ-TAC1) all of which can produce SP, while NKA and its N-terminally extended forms neuropeptide K and neuropeptide γ arise from β- and γ-TAC1 only. NKB is the only tachykinin derived from the TAC3 (PPT-B) gene. The human TAC4 (PPT-C) gene can yield several precursor proteins (α-, β-, γ- and δ-TAC4) which give rise to the tachykinins hemokinin-1, hemokinin-1(4-11), endokinin A and endokinin B and the tachykinin-like peptides endokinin C and endokinin D. While SP, NKA and NKB are conserved across mammalian species, the amino acid sequence of TAC4 gene-derived tachykinins differs considerably between humans and rodents.

The biological actions of tachykinins are brought about by three types of tachykinin receptor. Encoded by the genes TACR1, TACR2 and TACR3, they are currently named by the acronyms NK1, NK2 and NK3. These receptors are coupled through Gq and G11 to phospholipase C. The agonist potency profile at the NK1 receptor is SP>NKA>NKB, at the NK2 receptor NKA>NKB>SP, and at the NK3 receptor NKB>NKA>SP. Human hemokinin-1 and its N-terminally extended forms endokinin A and B act preferentially at NK1 receptors. Agonists with high selectivity for only one tachykinin receptor have been obtained by synthetic modification of the natural tachykinins. There are small species differences in the amino acid sequence of the tachykinin receptors, which has little impact on agonist activity, but entails that the affinity of many nonpeptide tachykinin receptor antagonists differs profoundly between humans and rodents.

Tachykinins are known to mediate excitatory neurotransmission in the CNS and periphery, cause arteriolar dilatation, hypotension and contraction of nonvascular smooth muscle, increase venular permeability, participate in immune and inflammatory responses and stimulate endocrine and exocrine gland secretion. NK1 receptors are widely expressed in peripheral tissues and the CNS. NK2 receptors predominate in the periphery, while NK3 receptors prevail in the CNS. The functional roles attributed to tachykinins in health and disease indicate that tachykinin receptors are important targets for novel medicines. This has led to the development of peptide-based and nonpeptide antagonists that are highly potent and selective for either the NK1, NK2 or NK3 receptor.

The quinuclidine CP-96345 was the first nonpeptide NK1 receptor antagonist reported by Pfizer in 1991, although its utility was limited by toxicity due to nonselective ion channel blockade. Subsequently, many other NK1 receptor antagonists based on piperidine, perhydroisoindole and related structures were developed, including CP-99994, CP-122721, CJ-11974/ezlopitant (Pfizer), MK-869/aprepitant, L-754,274 (Merck & Co.), GR-203040, GR-205171/vofopitant (Glaxo), SR-140333/Nolpitantium (Sanofi), RP-67580, RPR-100893/dapitant (Rhone-Poulenc) and LY-303870/lanepitant (Eli Lilly). In 2003, aprepitant was approved for the combination treatment of chemotherapy-induced emesis, whereas clinical studies addressing pain, migraine, inflammation and chronic obstructive pulmonary disease (COPD) have been disappointing. Although aprepitant reduced anxiety and depression in Phase II trials, its development for this condition was discontinued following negative Phase III studies. Other possible indications of NK1 receptor antagonists include skin disorders, inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS).

The first potent nonpeptide antagonist selective for NK2 receptors was SR-48968/saredutant (Sanofi). This compound has since been joined by many other nonpeptide compounds such as SR-144190 (Sanofi), GR-159897 (Glaxo), YM-38336 (Yamanouchi) and SB-414240 (SmithKlineBeecham) and by cyclic peptide-based compounds such as MEN-11420/nepadutant (Menarini). Although several of these compounds are in development for IBS, COPD, anxiety and depression, data on their therapeutic utility are not yet available.

The development of selective NK3 receptor antagonists began in 1993, when SR-142801/osanetant was discovered by Sanofi to be a high affinity nonpeptide antagonist at NK3 receptors. More selective than osanetant, though with lower affinity, are peptoids such as PD-161182 (Parke-Davis) or substituted quinuclidines such as SB-222200 and SB-223412/talnetant (SmithKlineBeecham). Clinical trials of osanetant in schizophrenia, of talnetant in COPD, and of SB-222200 in CNS disorders have been carried out. Other possible indications of NK3 receptor antagonists include somatic and visceral pain.

With regard to the treatment of COPD and pain there is increasing interest in combined tachykinin receptor antagonists. ZD-6021 (AstraZeneca), MDL-105212A (HoechstMarionRoussel) and DNK-333 (Novartis) are dual NK1/NK2 receptor antagonists, while MDL-105172A (HoechstMarionRoussel) and SCH-206272 (Schering-Plough) are triple NK1/NK2/NK3 receptor antagonists.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name NK1 NK2
Structural Information 407 aa (human) 398 aa (human) 465 aa (human)
Preferred Endogenous Peptide Substance P (S6883) Neurokinin A (N4267) Neurokinin B (N4143)
Subtype Selective Agonists Substance P methyl ester
[Sar9,Met(O2)11]-Substance P (S3672)
[β-Ala8]-Neurokinin A(4-10) (N147)
GR-64349 (G113)
Senktide (SML0764)
[MePhe7]-Neurokinin B
Subtype Selective Peptide Antagonists GR-82334 (G115)
L-659,877 (L117)
MEN-11420 (Nepadutant)
Subtype Selective Non-Peptide Antagonists L-703,606 (L119)
CP-99994a (SML0752)
FK888 (F1183)
RPR 100893
SR-140333 (Nolpitantium)
LY-303870 (Lanepitant)a
MK-869 (Aprepitant)a
SR-48968 (Saredutant)
SR-142801 (Osanetant)a
SB-223412 (Talnetant)
SB-222200 (S5192)
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG)
Radioligands of Choice [3H]-Substance P
[125I]-Neurokinin A
[3H]-SR 48968
[125I]-[MePhe7]-Neurokinin B
[3H]-SR 142801
Tissue Expression CNS (e.g. hippocampus, amygdala, hypothalamus, striatum, brainstem, dorsal horn of spinal cord)
Vascular endothelial cells
Inflammatory cells
Skin cells
Bronchial and intestinal smooth muscle
Enteric neurons
Some neurons in CNS
Inflammatory cells
Bronchial, gastrointestinal and urinary smooth muscle
CNS (e.g. hippocampus, hypothalamus, substantia nigra, brainstem, dorsal horn of spinal cord)
Enteric neurons
Physiological Function Central stress reactions, mood control, afferent neuron transmission, pain, airway and lung function, control of vascular diameter and permeability (neurogenic inflammation), immune modulation, control of intestinal secretion and motility Mood control, afferent nerve traffic, airway and lung function, gastrointestinal contraction CNS functions, afferent neuron transmission, control of intestinal motility and secretion
Disease Relevance Anxiety and depression, nausea and emesis, inflammatory hyperalgesia, inflammation, skin diseases, COPD, IBD, IBS, bladder hyperreflexia Anxiety and depression, COPD, visceral hyperalgesia, IBS, urinary incontinence Psychoses, schizophrenia, somatic and visceral hyperalgesia, COPD, IBS



a) Note that significant species differences exist.


CJ-11974: ((2S,3S-cis)-2-Diphenylmethyl)-N-1-azabicyclo-[2.2.2]octan-3-amine
CP-99994: (+)-(2S-3S)-3-(2-Methoxybenzylamino)-2-phenylpiperidine
CP-122721: (+)-2S,3S(-3-(2-Methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine)
FK888: (4R)-4-Hydroxy-l-[(l-methyl-lH-indol-3-yl)carbonyl]-L-prolyl-N-benzyl-N-methyl-3-(2-naphthyl)-L-alaninamide
GR-64349: Lys-Asp-Ser-Phe-Val-Gly-R-γ-lactam-Leu-Met-NH2
GR-82334: pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Pro spiro-γ-lactam-Leu-Trp-NH2
GR-71251: [D-Pro9,[spiro-γ-lactam]Leu10,Trp11]substance P
GR-159897: (R)-1-[2-(5-Fluoro-1H-indol-3-yl)ethyl]-4-methoxy-4[(phenylsulfinyl)-methyl]piperidine
GR-203040: (2S, 3S)-2-Methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine
GR-205171: 3(S)-(2-Methoxy-5(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine
L-659874: N-Acetyl-L-leucyl-L-methionyl-L-glutaminyl-L-tryptophyl-L-phenylalanyl-glycinamide
L-659877: Cyclo(Gln-Trp-Phe-Gly-Leu-Met)
L-703606: cis-2-(Diphenylmethyl)-N-([2-iodophenyl]methyl)-1-azabicyclo(2.2.2)octan-3-amine
L-733060: (2S,3S)3-([3,5-bis(Trifluoromethyl)phenyl]methoxy)-2-phenylpiperidine
L-668169: Cyclo(Gln-D-Trp(NMe)-Phe(R)Gly[ANC-2]Leu-Met)2
LY-303870: (R)-1-[N-(2-Methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(piperidin-1-yl)acetyl)amino]propane
MK-869: 2-(R)-(1-(R)-3,5-bis(Trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine
NKP-608: Quinoline-4-carboxylic acid [trans-(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)- piperidin-4-yl]-amide
PD-154075: [(2-Benzofuran)-CH2OCO]-(R)-α-MeTrp-(S)-NHCH(CH3)Ph
PD-161182: [(1R)-2-[[7-[(Aminocarbonyl)amino]heptyl]amino]-1-[(2,3-difluorophenyl)methyl]-1-methyl-2-oxoethyl]-carbamic acid (1S)-2-methyl-1-phenylpropyl ester
R486: H-Asp-Ser-Phe-Trp-β-Ala-Leu-Met-NH2
R820: (4R)-4-Hydroxy-1-(1H-indol-3-ylcarbonyl)-L-prolyl-N-methyl-2-phenyl-N-(phenylmethyl-(2S)-glycinamide
RP-67580: 2-[1-Imino-2-(2-methoxyphenyl)ethyl]-7,7-diphenyl-4-perhydroisoindolone-(3aR,7aR)
RPR-100893: (3aS,4S,7aS)-7,7-Diphenyl-4-(2-methoxyphenyl)-2[S-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol
SB-223412: (S)-N-(1-Phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide
SB-222200: (S)-(–)-(α-Ethylbenzyl)-3-methyl-2-phenylquinoline-4-carboxamide
SB-414240: (S)-(+)-N-(1,2,2-Trimethylpropyl)-3-[(4-piperidin-1-yl)piperidin-1-yl]methyl-2-phenylquinoline-4-carboxamide
SR-48968: (S)-N-Methyl-N[4-(4-acetylamino-4-[phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide
SR-140333: (S)-1-(2-[3,4-Dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride
SR-142801: (S)-(N)-(1-(3-(1-Benzoyl-3-(3,4-dichlorophenyl)piperidin-3-yl)propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide
SR-144190: (R)-3-{1-[2-(4-Benzoyl-2-(3,4-difluorophenyl)-morpholin-2-yl)-ethyl]-4-phenylpiperidin-4-yl}-1-dimethylurea


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