Target Validation Information
Target ID T72458
Target Name Melanocortin-4 receptor
Target Type
Clinical Trial
Drug Potency against Target Melanotetan II Drug Info Kd = 19 nM [552619]
Ac-dR[CEHdFRWC]-NH2 Drug Info Ki = 0.55 nM [527529]
Ac-YR[CEH(pCl-dF)RWC]-NH2 Drug Info Ki = 0.14 nM [527529]
C(his-D-phe-arg-trp-Ahx) Drug Info Ki = 670 nM [528187]
C(his-D-phe-arg-trp-Abu) Drug Info Ki = 5780 nM [528187]
C(his-D-phe-arg-trp-Ahp) Drug Info Ki = 244 nM [528187]
Ac-His-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 29 nM [528247]
MCL-129 Drug Info IC50 = 12.7 nM [528626]
Ac-His-DPhe-Arg-Trp-NH2 Drug Info IC50 = 1153 nM [534420]
1-Benzyl-4-methyl-piperazine Drug Info Ki = 2000 nM [527746]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 Drug Info IC50 = 0.6 nM [530169]
Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 Drug Info IC50 = 1.1 nM [530169]
His-DPhe-Arg-Trp Drug Info IC50 = 1100 nM [528799]
C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 2500 nM [528082]
C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro] Drug Info Ki = 173 nM [527997]
C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro] Drug Info IC50 = 22 nM [527997]
Tic-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 24 nM [527941]
ML-253764 Drug Info IC50 = 708 nM [527997]
Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg Drug Info IC50 = 5.9 nM [528799]
Ac-YR[CEH(pF-dF)RWC]-NH2 Drug Info Ki = 0.28 nM [527529]
Ac-YK[CEHdFRWC]-NH2 Drug Info Ki = 1.22 nM [527529]
GPYRMEHFRWGSPPKD-NH2 Drug Info Ki = 5.28 nM [527529]
Ac-YRMEHdFRWG-NH2 Drug Info Ki = 0.55 nM [527529]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 104 nM [528247]
C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 270 nM [528082]
C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 180 nM [528082]
C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 16 nM [528082]
C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 65 nM [528082]
C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 430 nM [529226]
Ac-YRMEHdFRWGSPPKD-NH2 Drug Info Ki = 0.27 nM [527529]
NDP-SYSMEHFRWGKPVG Drug Info Ki = 0.31 nM [527529]
Ac-[CEHdFRWC]-NH2 Drug Info Ki = 2.29 nM [527529]
C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 600 nM [528082]
C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 170 nM [528082]
C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 1000 nM [528082]
C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 2700 nM [528082]
C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2 Drug Info IC50 = 777 nM [529226]
MK-11 Drug Info Ki = 630 nM [526348]
MK-10 Drug Info Ki = 190 nM [526348]
Bremelanotide Drug Info Ki = 10 nM [552797]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [531079]
Ac-Phe-[Orn-Pro-cha-Trp-Arg] Drug Info IC50 = 400 nM [528343]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 Drug Info IC50 = 13000 nM [528343]
NDP-alpha-MSH Drug Info Ki = 0.47 nM [529789]
afamelanotide Drug Info IC50 = 19 nM [527610]
AEKKDEGPYRMEHFRWGSPPKD Drug Info Ki = 8.18 nM [527529]
Ac-YRC(Me)*EHdFRWC(Me)NH2 Drug Info Ki = 13.25 nM [527529]
Ac-R[CEHdFRWC]-NH2 Drug Info Ki = 0.44 nM [527529]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 Drug Info Ki = 0.3 nM [527529]
C(his-L-phe-arg-trp-Aoc) Drug Info Ki = 4420 nM [528187]
C(his-D-phe-arg-trp-Aoc) Drug Info Ki = 319 nM [528187]
Ac-YR[CEHFRWC]-NH2 Drug Info Ki = 30.51 nM [527529]
C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 34 nM [528082]
C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 77 nM [528082]
C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 150 nM [528082]
C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 100 nM [528082]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2 Drug Info IC50 = 33 nM [530169]
AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2 Drug Info IC50 = 11 nM [530169]
Ac-YR[CEHdFRWC]SPPKD-NH2 Drug Info Ki = 0.52 nM [527529]
Ac-YR[CE(1-Me-H)dFRWC]-NH2 Drug Info Ki = 6.6 nM [527529]
Ac-YCit[CEHdFRWC]-NH2 Drug Info Ki = 2.54 nM [527529]
Ac-YR[CEHdFRWC]-NH2 Drug Info Ki = 0.77 nM [527529]
C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 170 nM [528082]
C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2 Drug Info IC50 = 930 nM [529226]
C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 300 nM [529226]
C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 330 nM [529226]
1-Methyl-4-(1-phenyl-ethyl)-piperazine Drug Info Ki = 700 nM [527746]
Action against Disease Model Bremelanotide Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA [552743] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations Increased food intake, weight and body fat [552619]
References
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Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 528247Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73.Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists.
Ref 528626Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005. Epub 2006 Dec 30.Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor.
Ref 534420J Med Chem. 1997 Jul 4;40(14):2133-9.Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R.
Ref 527746Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives.
Ref 530169J Med Chem. 2009 Jun 25;52(12):3627-35.Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor.
Ref 530169J Med Chem. 2009 Jun 25;52(12):3627-35.Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor.
Ref 528799Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. Epub 2007 Apr 6.Squalene-derived flexible linkers for bioactive peptides.
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Ref 527997J Med Chem. 2006 Feb 9;49(3):911-22.Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation.
Ref 527997J Med Chem. 2006 Feb 9;49(3):911-22.Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation.
Ref 527941Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5. Epub 2005 Dec 20.Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists.
Ref 527997J Med Chem. 2006 Feb 9;49(3):911-22.Mapping the binding site of melanocortin 4 receptor agonists: a hydrophobic pocket formed by I3.28(125), I3.32(129), and I7.42(291) is critical for receptor activation.
Ref 528799Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. Epub 2007 Apr 6.Squalene-derived flexible linkers for bioactive peptides.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528247Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73.Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 526348J Med Chem. 2002 Jun 6;45(12):2644-50.Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors.
Ref 526348J Med Chem. 2002 Jun 6;45(12):2644-50.Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors.
Ref 552797Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov. 2008 Apr;7(4):307-23. doi: 10.1038/nrd2331.
Ref 531079J Med Chem. 2010 Sep 9;53(17):6386-97.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 receptor agonist with unprecedented selectivity and procognitive potential.
Ref 528343Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. Epub 2006 Jul 28.Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivoactivity.
Ref 528343Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92. Epub 2006 Jul 28.Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivoactivity.
Ref 552743Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med. 2007 Nov;4 Suppl 4:269-79.
Ref 529789J Med Chem. 2008 Nov 27;51(22):7094-8.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 responses against carrageenan-induced hyperalgesia.
Ref 527610Bioorg Med Chem Lett. 2005 Aug 1;15(15):3501-5.Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 528187Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6. Epub 2006 May 5.Design of cyclic peptides with agonist activity at melanocortin receptor-4.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 530169J Med Chem. 2009 Jun 25;52(12):3627-35.Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor.
Ref 530169J Med Chem. 2009 Jun 25;52(12):3627-35.Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 receptor.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 527529J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist.
Ref 528082J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 529226J Med Chem. 2008 Jan 24;51(2):187-95. Epub 2007 Dec 19.Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 receptor.
Ref 527746Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives.

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