Target Validation Information
TTD ID T72458
Target Name Melanocortin receptor 4 (MC4R)
Type of Target
Successful
Drug Potency against Target Bremelanotide Drug Info Ki = 10 nM [20]
Melanotetan II Drug Info Kd = 19 nM [18]
1-Benzyl-4-methyl-piperazine Drug Info Ki = 2000 nM [4]
1-Methyl-4-(1-phenyl-ethyl)-piperazine Drug Info Ki = 700 nM [4]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki < 1000 nM [16]
Ac-dR[CEHdFRWC]-NH2 Drug Info Ki = 0.55 nM [2]
Ac-His-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 29 nM [9]
Ac-His-DPhe-Arg-Trp-NH2 Drug Info IC50 = 1153 nM [17]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2 Drug Info IC50 = 33 nM [15]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2 Drug Info IC50 = 0.6 nM [15]
AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2 Drug Info IC50 = 11 nM [15]
Ac-R[CEHdFRWC]-NH2 Drug Info Ki = 0.44 nM [2]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 104 nM [9]
Ac-YCit[CEHdFRWC]-NH2 Drug Info Ki = 2.54 nM [2]
Ac-YK[CEHdFRWC]-NH2 Drug Info Ki = 1.22 nM [2]
Ac-YRC(Me)*EHdFRWC(Me)NH2 Drug Info Ki = 13.25 nM [2]
Ac-YRMEHdFRWG-NH2 Drug Info Ki = 0.55 nM [2]
Ac-YRMEHdFRWGSPPKD-NH2 Drug Info Ki = 0.27 nM [2]
Ac-YR[CE(1-Me-H)dFRWC]-NH2 Drug Info Ki = 6.6 nM [2]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2 Drug Info Ki = 0.3 nM [2]
Ac-YR[CEH(pCl-dF)RWC]-NH2 Drug Info Ki = 0.14 nM [2]
Ac-YR[CEH(pF-dF)RWC]-NH2 Drug Info Ki = 0.28 nM [2]
Ac-YR[CEHdFRWC]-NH2 Drug Info Ki = 0.77 nM [2]
Ac-YR[CEHdFRWC]SPPKD-NH2 Drug Info Ki = 0.52 nM [2]
Ac-YR[CEHFRWC]-NH2 Drug Info Ki = 30.51 nM [2]
Ac-[CEHdFRWC]-NH2 Drug Info Ki = 2.29 nM [2]
AEKKDEGPYRMEHFRWGSPPKD Drug Info Ki = 8.18 nM [2]
Afamelanotide Drug Info IC50 = 19 nM [3]
C(his-D-phe-arg-trp-Abu) Drug Info Ki = 5780 nM [8]
C(his-D-phe-arg-trp-Ahp) Drug Info Ki = 244 nM [8]
C(his-D-phe-arg-trp-Ahx) Drug Info Ki = 670 nM [8]
C(his-D-phe-arg-trp-Aoc) Drug Info Ki = 319 nM [8]
C(his-L-phe-arg-trp-Aoc) Drug Info Ki = 4420 nM [8]
C[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 300 nM [13]
C[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2 Drug Info IC50 = 930 nM [13]
C[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 330 nM [13]
C[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2 Drug Info IC50 = 430 nM [13]
C[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2 Drug Info IC50 = 777 nM [13]
C[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 77 nM [7]
C[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 270 nM [7]
C[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 170 nM [7]
C[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 150 nM [7]
C[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 65 nM [7]
C[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 34 nM [7]
C[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 100 nM [7]
C[Nle-His-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 170 nM [7]
C[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 16 nM [7]
C[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 600 nM [7]
C[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 1000 nM [7]
C[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 2700 nM [7]
C[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2 Drug Info IC50 = 180 nM [7]
C[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2 Drug Info IC50 = 2500 nM [7]
C[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro] Drug Info Ki = 173 nM [6]
C[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro] Drug Info IC50 = 22 nM [6]
GPYRMEHFRWGSPPKD-NH2 Drug Info Ki = 5.28 nM [2]
His-DPhe-Arg-Trp Drug Info IC50 = 1100 nM [12]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2 Drug Info IC50 = 13000 nM [10]
MCL-129 Drug Info IC50 = 12.7 nM [11]
MK-10 Drug Info Ki = 190 nM [1]
MK-11 Drug Info Ki = 630 nM [1]
ML-253764 Drug Info IC50 = 708 nM [6]
MT-II Drug Info IC50 = 1.1 nM [15]
NDP-alpha-MSH Drug Info Ki = 0.47 nM [14]
NDP-SYSMEHFRWGKPVG Drug Info Ki = 0.31 nM [2]
PMX-53 Drug Info IC50 = 400 nM [10]
Ser-Tyr-Ser-Nle-Glu-His-Dphe-Arg Drug Info IC50 = 5.9 nM [12]
Tic-D-Phe-Arg-2-Nal-NHCH3 Drug Info Ki = 24 nM [5]
Action against Disease Model Bremelanotide Drug Info 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 [19]
References
REF 1 Novel cyclic templates of alpha-MSH give highly selective and potent antagonists/agonists for human melanocortin-3/4 receptors. J Med Chem. 2002 Jun 6;45(12):2644-50.
REF 2 Discovery of a beta-MSH-derived MC-4R selective agonist. J Med Chem. 2005 May 5;48(9):3095-8.
REF 3 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-oxo... Bioorg Med Chem Lett. 2005 Aug 1;15(15):3501-5.
REF 4 Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives. Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.
REF 5 Synthesis of Tic-D-Phe Psi[CH2-CH2] isostere and its use in the development of melanocortin receptor agonists. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1721-5.
REF 6 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... J Med Chem. 2006 Feb 9;49(3):911-22.
REF 7 Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. J Med Chem. 2006 Mar 23;49(6):1946-52.
REF 8 Design of cyclic peptides with agonist activity at melanocortin receptor-4. Bioorg Med Chem Lett. 2006 Jul 15;16(14):3723-6.
REF 9 Design and synthesis of potent and selective 1,3,4-trisubstituted-2-oxopiperazine based melanocortin-4 receptor agonists. Bioorg Med Chem Lett. 2006 Sep 1;16(17):4668-73.
REF 10 Peptidomimetic C5a receptor antagonists with hydrophobic substitutions at the C-terminus: increased receptor specificity and in vivo activity. Bioorg Med Chem Lett. 2006 Oct 1;16(19):5088-92.
REF 11 Structure-activity relationships of novel piperazines as antagonists for the melanocortin-4 receptor. Bioorg Med Chem. 2007 Mar 1;15(5):1989-2005.
REF 12 Squalene-derived flexible linkers for bioactive peptides. Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3.
REF 13 Structure-activity relationships of cyclic lactam analogues of alpha-melanocyte-stimulating hormone (alpha-MSH) targeting the human melanocortin-3 ... J Med Chem. 2008 Jan 24;51(2):187-95.
REF 14 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.
REF 15 Substitution of arginine with proline and proline derivatives in melanocyte-stimulating hormones leads to selectivity for human melanocortin 4 rece... J Med Chem. 2009 Jun 25;52(12):3627-35.
REF 16 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.
REF 17 Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. J Med Chem. 1997 Jul 4;40(14):2133-9.
REF 18 Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site. Curr Top Med Chem. 2006;6(11):1173-82.
REF 19 Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med. 2007 Nov;4 Suppl 4:269-79.
REF 20 Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. Nat Rev Drug Discov. 2008 Apr;7(4):307-23.

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