Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTZPO1L)

• DTT Name: Substance-P receptor (TACR1)
• Synonyms: Tachykinin receptor 1; Tachykinin neurokinin 1 receptor; Tachykinin 1 receptor; TACR1; Substance P receptor; SPR; Neurokinin 1 receptor; NK-1R; NK-1 receptor
• Gene Name: TACR1
• DTT Type: Successful target; [1]
• Related Disease:
  Depression [ICD-11: 6A70-6A7Z]
  Nausea/vomiting [ICD-11: MD90]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: NK1R_HUMAN
• TTD ID: T47094
• Sequence:
  MDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIVVTSVVGNVVVMWIILAH
  KRMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGLFYCKFHNFFPIAAVFASI
  YSMTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALLLAFPQGYYSTTETMPSRVVC
  MIEWPEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTVVGITLWASEIPGDSSDRYHEQV
  SAKRKVVKMMIVVVCTFAICWLPFHIFFLLPYINPDLYLKKFIQQVYLAIMWLAMSSTMY
  NPIIYCCLNDRFRLGFKHAFRCCPFISAGDYEGLEMKSTRYLQTQGSVYKVSRLETTIST
  VVGAHEEEPEDGPKATPSSLDLTSNCSSRSDSKTMTESFSFSSNVLS
• Function: This is a receptor for the tachykinin neuropeptide substance P. It is probably associated with G proteins that activate a phosphatidylinositol-calcium second messenger system. The rank order of affinity of this receptor to tachykinins is: substance P > substance K > neuromedin-K.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Measles (hsa05162)
• Reactome Pathway: G alpha (q) signalling events (R-HSA-416476)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aprepitant	DM053KT	Depression	6A70-6A7Z	Approved	[1]
Palonosetron + fosnetupitant	DMK2PBD	Chemotherapy-induced nausea	MD90	Approved	[2]
Rolapitant	DM8XP26	Chemotherapy-induced nausea	MD90	Approved	[3]
Selegiline	DM6034S	Major depressive disorder	6A70.3	Approved	[4]

18 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY-686017	DM7WORZ	Atopic dermatitis	EA80	Phase 3	[5]
Netupitant	DMEKAYI	Chemotherapy-induced nausea	MD90	Phase 3	[3]
Serlopitant	DM5VH6U	Prurigo nodularis	EC91.0	Phase 3	[6]
CP-122721	DMSWLM5	Major depressive disorder	6A70.3	Phase 2	[7]
DAPITANT	DMR5J6K	Pain	MG30-MG3Z	Phase 2	[8], [9]
FR139317	DMEL5SV	Hypertension	BA00-BA04	Phase 2	[4]
GW 597599	DMY53PL	Major depressive disorder	6A70.3	Phase 2	[10]
LANEPITANT	DM1VK96	Pain	MG30-MG3Z	Phase 2	[11], [9]
LY-2590443	DM81UJW	Migraine	8A80	Phase 2	[12]
NKP 608	DMTVGMZ	Mood disorder	6A60-6E23	Phase 2	[13]
Orvepitant	DMSO846	Anxiety disorder	6B00-6B0Z	Phase 2	[4]
SCH-900978	DMPBKUZ	Cough	MD12	Phase 2	[14]
SSR240600	DMVZ01T	Urinary incontinence	MF50.2	Phase 2	[15]
TKA-731	DMT8SMO	Pain	MG30-MG3Z	Phase 2	[16]
VOFOPITANT HYDROCHLORIDE	DMQMYP5	Vomiting	MD90	Phase 2	[17], [9]
CJ-12255	DMRQX9H	Eczema	EA80-EA89	Phase 1	[18], [9]
Figopitant	DMLH2Q6	Diabetic complication	5A2Y	Phase 1	[19]
GSK1144814	DMK3S9J	Alcohol dependence	6C40.2	Phase 1	[20]

28 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Casopitant	DMBQYO0	Chemotherapy-induced nausea	MD90	Withdrawn from market	[21]
BL-1832	DMLXHZR	Pain	MG30-MG3Z	Discontinued in Phase 3	[22]
L-759274	DMXWRGF	Depression	6A70-6A7Z	Discontinued in Phase 3	[21]
CGP-49823	DMBJQU6	Pain	MG30-MG3Z	Discontinued in Phase 2	[23]
CS-003	DM1AEVT	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[24]
DNK-333	DM4ZO01	Irritable bowel syndrome	DD91.0	Discontinued in Phase 2	[25]
Ezlopitant	DMTUPZ2	Irritable bowel syndrome	DD91.0	Discontinued in Phase 2	[26], [27]
FK-224	DM1JUS0	Asthma	CA23	Discontinued in Phase 2	[28], [29], [30]
FK-888	DM457B1	Migraine	8A80	Discontinued in Phase 2	[31]
GSK 679769	DMSV6KP	Anxiety disorder	6B00-6B0Z	Discontinued in Phase 2	[26]
Nolpitantium besilate	DMK5WLZ	Asthma	CA23	Discontinued in Phase 2	[32]
TA-5538	DMBZG2Y	Overactive bladder	GC50.0	Discontinued in Phase 2	[33]
TAK-637	DMDVJKW	Depression	6A70-6A7Z	Discontinued in Phase 2	[21]
AVE-5883	DM3P84V	Asthma	CA23	Discontinued in Phase 1/2	[34]
SDZ-NKT-343	DM8C3G5	Pain	MG30-MG3Z	Discontinued in Phase 1	[35]
SLV-323	DMHRYX6	Chemotherapy-induced nausea	MD90	Discontinued in Phase 1	[26]
CI-1021	DMUK9L4	N. A.	N. A.	Terminated	[36]
CP-96345	DM4HYWR	N. A.	N. A.	Terminated	[37]
FK-355	DMIGXQF	Asthma	CA23	Terminated	[29]
FR-113680	DMCAZPR	Asthma	CA23	Terminated	[38]
GR-82334	DMR2TZK	Vomiting	MD90	Terminated	[39]
L-732138	DMVXKMF	N. A.	N. A.	Terminated	[40]
L-733060	DMA1NJW	N. A.	N. A.	Terminated	[41]
L-741671	DMRVXEQ	Vomiting	MD90	Terminated	[42]
MEN-11149	DMEYNB0	Asthma	CA23	Terminated	[43]
MEN-11467	DMNTIWC	Respiratory tract inflammation	CA07	Terminated	[44]
RP-67580	DMDLW64	Pain	MG30-MG3Z	Terminated	[45]
WIN-64821	DM960I8	Asthma	CA23	Terminated	[46]

64 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(D)-Phe-(D)-Phe-NH2	DM5ZIUW	Discovery agent	N.A.	Investigative	[47]
(D)-Phe-(L)-Phe-NH2	DMS32YA	Discovery agent	N.A.	Investigative	[47]
(L)-Phe-(D)-Phe-NH2	DMP9ZVQ	Discovery agent	N.A.	Investigative	[47]
2-Phenyl-3-(1-phenyl-ethoxy)-piperidine	DMNXI6D	Discovery agent	N.A.	Investigative	[41]
3,6-Diphenyl-1-oxa-7-aza-spiro[4.5]decane	DMEOBNJ	Discovery agent	N.A.	Investigative	[48]
3-Benzyloxy-2-phenyl-piperidine	DM94K83	Discovery agent	N.A.	Investigative	[41]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[49]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (3,5-BIS-TRIFLUOROMETHYL-BENZYL)-METHYL-AMIDE (STRUCTURAL MIX)	DMMENDC	Discovery agent	N.A.	Investigative	[50]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (S)-[(R)-1-(3,5-BIS-TRIFLUOROMETHYL-PHENYL)-ETHYL]-METHYL-AMIDE (ENANTIOMERIC MIX)	DMO0RGL	Discovery agent	N.A.	Investigative	[50]
7-METHYL-8-OXO-5-P-TOLYL-7,8-DIHYDRO-[1,7]NAPHTHYRIDINE-6-CARBOXYLIC ACID (S)-[(S)-1-(3,5-BIS-TRIFLUOROMETHYL-PHENYL)-ETHYL]-METHYL-AMIDE (ENANTIOMERIC MIX)	DMOAJ0E	Discovery agent	N.A.	Investigative	[50]
Ac-Phe-Phe-NH2	DMDXBQA	Discovery agent	N.A.	Investigative	[47]
Arg-Pro-Lys-Pro-Ala-Gln-Phe-Phe-Gly-Leu-Met-NH2	DM6PA1S	Discovery agent	N.A.	Investigative	[51]
Arg-Pro-Lys-Pro-Ala-Ser-Phe-Phe-Gly-Leu-Met-NH2	DMYM91S	Discovery agent	N.A.	Investigative	[51]
Arg-Pro-Lys-Pro-Gln-Ser-Phe-Phe-Gly-Leu-Met-NH2	DMA318X	Discovery agent	N.A.	Investigative	[51]
befetupitant	DMZX57Y	Discovery agent	N.A.	Investigative	[52]
CP-100263	DMLFNTH	Vomiting	MD90	Investigative	[26]
CP-99,994	DMVJX21	Discovery agent	N.A.	Investigative	[36]
eledoisin	DMEOJ9W	Discovery agent	N.A.	Investigative	[53]
ENDOMORPHIN 2	DMOQWBU	Discovery agent	N.A.	Investigative	[47]
EU-C-001	DMR3487	Brain injury	NA07.Z	Investigative	[12]
H-Ala-Pro-Phe-Phe-NH2	DM5S4AO	Discovery agent	N.A.	Investigative	[47]
H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH	DMJ6N1X	Discovery agent	N.A.	Investigative	[47]
H-Leu-Phe-NH2	DMAPWC2	Discovery agent	N.A.	Investigative	[47]
H-Phe-NH2	DM9IODG	Discovery agent	N.A.	Investigative	[47]
H-Phe-Phe-NH2	DM0KFW2	Discovery agent	N.A.	Investigative	[47]
H-Pro-Phe-Phe-NH2	DMXKPQR	Discovery agent	N.A.	Investigative	[47]
H-Tyr(OMe)-Phe(2-Me)-NH2	DMX08FL	Discovery agent	N.A.	Investigative	[47]
H-Tyr-Ala-Phe-Phe-NH2	DMUHBGC	Discovery agent	N.A.	Investigative	[47]
H-Tyr-D-Ala-Gly Phe-Pro-Leu-Trp-O-3,5-Bzl(CF3)2	DMDF9AS	Discovery agent	N.A.	Investigative	[54]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-3,5-Bzl(CF3)2	DM2K16M	Discovery agent	N.A.	Investigative	[54]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl	DMRE4ZI	Discovery agent	N.A.	Investigative	[54]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NMe-3,5-Bzl(CF3)2	DM1ESMZ	Discovery agent	N.A.	Investigative	[54]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NMe-Bzl	DM56KDV	Discovery agent	N.A.	Investigative	[54]
H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-O-Bzl	DMH3YKR	Discovery agent	N.A.	Investigative	[54]
H-Tyr-Pro-Ala-Phe-NH2	DMP0CRD	Discovery agent	N.A.	Investigative	[47]
H-Tyr-Pro-Phe-Ala-NH2	DM2F6L9	Discovery agent	N.A.	Investigative	[47]
H-Tyr-Pro-Phe-Phe-OH	DMUQLRN	Discovery agent	N.A.	Investigative	[47]
Homspera	DMI7258	Influenza virus infection	1E30-1E32	Investigative	[12]
kassinin	DMMIA38	Discovery agent	N.A.	Investigative	[53]
L-703,606	DMUOPRT	Discovery agent	N.A.	Investigative	[53]
L-708568	DMLMV9P	Discovery agent	N.A.	Investigative	[55]
L-736281	DMJNLSI	Discovery agent	N.A.	Investigative	[42]
MDL-28163	DMUHJ2C	Discovery agent	N.A.	Investigative	[56]
neurokinin A	DM9UXRP	Discovery agent	N.A.	Investigative	[57]
physalaemin	DM09T76	Discovery agent	N.A.	Investigative	[53]
Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2	DMOTXE3	Discovery agent	N.A.	Investigative	[51]
R-226161	DM4BP7S	Discovery agent	N.A.	Investigative	[58]
R116031	DM6Y7QM	Discovery agent	N.A.	Investigative	[59]
S-41744	DMFC430	Major depressive disorder	6A70.3	Investigative	[12]
SCH 206272	DMD1M24	Discovery agent	N.A.	Investigative	[60]
Septide	DMRJIP4	Discovery agent	N.A.	Investigative	[61]
SP-SAP	DMKCJQW	Cancer related pain	MG30	Investigative	[12]
SPANTIDE	DMV63IP	Discovery agent	N.A.	Investigative	[62]
spantide II	DMKC6IX	Discovery agent	N.A.	Investigative	[63]
Substance P	DMQ6W4I	Discovery agent	N.A.	Investigative	[64]
T2328	DMCWE90	Discovery agent	N.A.	Investigative	[65]
Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl	DMWOP9N	Discovery agent	N.A.	Investigative	[66]
WIN-64745	DMQ1B2Y	Discovery agent	N.A.	Investigative	[67]
WIN-66306	DMUM5LV	Discovery agent	N.A.	Investigative	[68]
WIN-68577	DMJHG1O	Discovery agent	N.A.	Investigative	[68]
ZD-6021	DM8MXS6	Discovery agent	N.A.	Investigative	[69], [69], [70]
[125I]L703,606	DMKSI80	Discovery agent	N.A.	Investigative	[71]
[18F]SPA-RQ	DMXIO84	Discovery agent	N.A.	Investigative	[12]
[Sar9,Met(O2)11]-SP	DMYF85Q	Discovery agent	N.A.	Investigative	[72]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Schizophrenia	6A20	Pre-frontal cortex	7.40E-01	0.02	0.07
Schizophrenia	6A20	Superior temporal cortex	8.57E-01	-0.02	-0.18
Chronic obstructive pulmonary disease	CA23	Lung tissue	9.59E-02	-0.05	-0.28
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	1.38E-01	0.05	0.3
Irritable bowel syndrome	DD91.0	Rectal colon tissue	1.94E-01	0.04	0.2
Asthma	CA23	Nasal and bronchial airway	9.91E-01	0.02	0.09
Major depressive disorder	6A20	Pre-frontal cortex	7.24E-01	0.02	0.11

References

• [1] Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists. J Med Chem. 2009 May 14;52(9):3039-46.
• [2] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [3] Netupitant and palonosetron trigger NK1 receptor internalization in NG108-15 cells. Exp Brain Res. 2014 Aug;232(8):2637-44.
• [4] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [5] Stress-related neuropeptides and alcoholism: CRH, NPY and beyond. Alcohol. 2009 November; 43(7): 491-498.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] A review of drug options in age-related macular degeneration therapy and potential new agents. Expert Opin Pharmacother. 2006 Dec;7(17):2355-68.
• [8] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004225)
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [10] Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant). Magn Reson Chem. 2010 Jul;48(7):523-30.
• [11] NK1 receptor antagonists as a new treatment for corneal neovascularization. Invest Ophthalmol Vis Sci. 2014 Sep 16;55(10):6783-94.
• [12] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 360).
• [13] Neurokinin-1-receptor antagonism decreases anxiety and emotional arousal circuit response to noxious visceral distension in women with irritable bowel syndrome: a pilot study. Aliment Pharmacol Ther.2012 Feb;35(3):360-7.
• [14] Clinical pipeline report, company report or official report of OPKO Health, Inc.
• [15] SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]- 4-piperidinyl)-2-methylpropanamide], a centrally active nonpeptide antagonist of the tachykinin neurokinin-1 receptor: I. biochemical and pharmacological characterization. J Pharmacol Exp Ther. 2002 Dec;303(3):1171-9.
• [16] The NK1-receptor antagonist TKA731 in painful diabetic neuropathy: a randomised, controlled trial. Eur J Pain. 2006 Aug;10(6):567-71.
• [17] Efficacy and safety of casopitant mesylate, a neurokinin 1 (NK1)-receptor antagonist, in prevention of chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenicchemotherapy: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009 Jun;10(6):549-58.
• [18] Neurokinin-1 receptor, a new modulator of lymphangiogenesis in obese-asthma phenotype. Life Sci. 2013 Aug 6;93(4):169-77.
• [19] Investigation of figopitant and its metabolites in rat tissue by combining whole-body autoradiography with liquid extraction surface analysis mass spectrometry. Drug Metab Dispos. 2012 Mar;40(3):419-25.
• [20] Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.Br J Clin Pharmacol.2013 May;75(5):1328-39.
• [21] Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.
• [22] WO patent application no. 2006,0132,05, Neurokinin-1 receptor antagonists for the treatment of conditions responsive to testosterone elevation.
• [23] The potency of the novel tachykinin receptor antagonist CGP49823 at rat and gerbil motoneurones in vitro. Eur J Pharmacol. 1998 Jan 26;342(2-3):203-8.
• [24] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [25] Dual tachykinin NK1/NK2 antagonist DNK333 inhibits neurokinin A-induced bronchoconstriction in asthma patients. Eur Respir J. 2004 Jan;23(1):76-81.
• [26] Emerging drugs for chemotherapy-induced emesis. Expert Opin Emerg Drugs. 2006 Mar;11(1):137-51.
• [27] Targeting pain-depressed behaviors in preclinical assays of pain and analgesia: drug effects on acetic acid-depressed locomotor activity in ICR mice. Life Sci. 2009 Aug 12;85(7-8):309-15.
• [28] Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerv... J Pharmacol Exp Ther. 1992 Jul;262(1):403-8.
• [29] FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. J Pharmacol Exp Ther. 1992 Jul;262(1):398-402.
• [30] [Discovery and pharmacological properties of selective neurokinin-receptor antagonists, FK224 and FK888].Nihon Yakurigaku Zasshi.1995 Sep;106(3):193-204.
• [31] Pharmacological profile of a high affinity dipeptide NK1 receptor antagonist, FK888. Br J Pharmacol. 1992 Nov;107(3):785-9.
• [32] SR 140333, a novel, selective, and potent nonpeptide antagonist of the NK1 tachykinin receptor: characterization on the U373MG cell line. J Neurochem. 1994 Apr;62(4):1399-407.
• [33] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021639)
• [34] Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma. Am J Respir Crit Care Med. 2007 Mar 1;175(5):450-7.
• [35] The effects of SDZ NKT 343, a potent NK1 receptor antagonist, on cutaneous responses of primate spinothalamic tract neurones sensitized by intradermal capsaicin injection. Exp Brain Res. 1998 Aug;121(3):355-8.
• [36] Gabapentin and the neurokinin(1) receptor antagonist CI-1021 act synergistically in two rat models of neuropathic pain. J Pharmacol Exp Ther. 2002 Nov;303(2):730-5.
• [37] 2-Aryl-1-azabicyclo[2.2.2]octanes as novel nonpeptide substance P antagonists, Bioorg. Med. Chem. Lett. 4(6):839-842 (1994).
• [38] FR 113680: a novel tripeptide substance P antagonist with NK1 receptor selectivity. Br J Pharmacol. 1992 May;106(1):123-6.
• [39] Effect of the NK-1 receptor antagonist GR 82,334 on reflexly-induced bladder contractions. Life Sci. 1992;51(26):PL277-80.
• [40] The biological activity and metabolic stability of peptidic bifunctional compounds that are opioid receptor agonists and neurokinin-1 receptor anta... Bioorg Med Chem. 2009 Oct 15;17(20):7337-43.
• [41] 3-Benzyloxy-2-phenylpiperidine NK1 antagonists: the influence of alpha methyl substitution, Bioorg. Med. Chem. Lett. 7(23):2959-2962 (1997).
• [42] N-heteroaryl-2-phenyl-3-(benzyloxy)piperidines: a novel class of potent orally active human NK1 antagonists. J Med Chem. 1996 Jul 19;39(15):2907-14.
• [43] Pharmacology of the peptidomimetic, MEN 11149, a new potent, selective and orally effective tachykinin NK1 receptor antagonist. Eur J Pharmacol. 1998 Jan 12;341(2-3):201-9.
• [44] Effect of the long-acting tachykinin NK(1) receptor antagonist MEN 11467 on tracheal mucus secretion in allergic ferrets. Br J Pharmacol. 2001 Jan;132(1):189-96.
• [45] Effects of RP 67580, a tachykinin NK1 receptor antagonist, on a primary afferent-evoked response of ventral roots in the neonatal rat spinal cord. Br J Pharmacol. 1994 Dec;113(4):1141-6.
• [46] WIN 64821, a novel neurokinin antagonist produced by an Aspergillus sp. II. Biological activity. J Antibiot (Tokyo). 1994 Apr;47(4):399-410.
• [47] Discovery of dipeptides with high affinity to the specific binding site for substance P1-7. J Med Chem. 2010 Mar 25;53(6):2383-9.
• [48] Spirocyclic NK(1) antagonists II: [4.5]-spiroethers. Bioorg Med Chem Lett. 2002 Oct 7;12(19):2719-22.
• [49] Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [50] Axially chiral N-benzyl-N,7-dimethyl-5-phenyl-1, 7-naphthyridine-6-carboxamide derivatives as tachykinin NK1 receptor antagonists: determination of... J Med Chem. 1998 Oct 22;41(22):4232-9.
• [51] Conformational comparisons of a series of tachykinin peptide analogs. J Med Chem. 2007 Dec 27;50(26):6501-6.
• [52] Design and synthesis of a novel, achiral class of highly potent and selective, orally active neurokinin-1 receptor antagonists. Bioorg Med Chem Lett. 2006 Mar 1;16(5):1362-5.
• [53] The unpredicted high affinities of a large number of naturally occurring tachykinins for chimeric NK1/NK3 receptors suggest a role for an inhibitory domain in determining receptor specificity. J BiolChem. 1996 Aug 23;271(34):20250-7.
• [54] A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are delta/mu opioid ... J Med Chem. 2008 Mar 13;51(5):1369-76.
• [55] N-acyl-L-tryptophan benzyl esters: potent substance P receptor antagonists. J Med Chem. 1993 Jul 9;36(14):2044-5.
• [56] Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
• [57] Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. J Pharmacol Exp Ther.1997 Jun;281(3):1303-11.
• [58] Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-a... Bioorg Med Chem. 2007 Jun 1;15(11):3649-60.
• [59] Pharmacological profile of (2R-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-acetamide (S)-Hydroxybutanedioate (R116301), an orally and centrally active neurokinin-1 receptor antagonist. J Pharmacol Exp Ther. 2002 Aug;302(2):696-709.
• [60] SCH 206272: a potent, orally active tachykinin NK(1), NK(2), and NK(3) receptor antagonist. Eur J Pharmacol. 2002 Aug 23;450(2):191-202.
• [61] Septide: an agonist for the NK1 receptor acting at a site distinct from substance P. Mol Pharmacol. 1994 Feb;45(2):287-93.
• [62] Synthesis and substance P antagonist activity of naphthimidazolium derivatives. J Med Chem. 1992 Apr 3;35(7):1273-9.
• [63] Spantide II, an effective tachykinin antagonist having high potency and negligible neurotoxicity. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4833-5.
• [64] Synthesis and structure-activity relationships of CP-122,721, a second-generation NK-1 receptor antagonist. Bioorg Med Chem Lett. 1998 Feb 3;8(3):281-4.
• [65] Pharmacological characterization of T-2328, 2-fluoro-4'-methoxy-3'-[[[(2S,3S)-2-phenyl-3-piperidinyl]amino]methyl]-[1,1'-biphenyl]-4-carbonitrile d... J Pharmacol Sci. 2008 Jan;106(1):121-7.
• [66] The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokin... J Med Chem. 2008 Oct 23;51(20):6334-47.
• [67] DOI: 10.1021/jo00074a031
• [68] WIN 66306, a new neurokinin antagonist produced by an Aspergillus species: fermentation, isolation and physico-chemical properties. J Antibiot (Tokyo). 1994 Nov;47(11):1182-7.
• [69] Pharmacological characterization of ZD6021: a novel, orally active antagonist of the tachykinin receptors. J Pharmacol Exp Ther. 2001 Jul;298(1):307-15.
• [70] Molecular cloning, mutations and effects of NK1 receptor antagonists reveal the human-like pharmacology of gerbil NK1 receptors.Biochem Pharmacol.2007 Jan 15;73(2):259-69.
• [71] Radioiodinated L-703,606: a potent, selective antagonist to the human NK1 receptor. Appl Radiat Isot. 1994 Jan;45(1):97-103.
• [72] cis-4-(Piperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydrobenzofuro[2,3-h]quinazolin-2-amine (A-987306), a new histamine H4R antagonist that blocks pain... J Med Chem. 2008 Nov 27;51(22):7094-8.