Therapeutic Targets Database
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Target Validation Information
TTD IDTTDC00072
Target NameMelanocortin-4 receptor    
Type of TargetClinical trial target    
Drug Potency against TargetBremelanotideKi = 10 nM[1]
Melanotetan IIIC50 = 20 nM[2]
Melanotetan IIKd = 19 nM[3]
Ac-Nle-c[Asp-His-DNal(2')-Pro-Trp-Lys]-NH2IC50 = 0.6 nM[4]
Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2IC50 = 1.07 nM[5]
Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2IC50 = 1.1 nM[4]
c[Nle-His-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 100 nM[6]
c[Nle-Pro-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 1000 nM[6]
AC-Nle-c[Asp-His-DPhe-Pro-Trp-Lys]-NH2IC50 = 11 nM[4]
His-DPhe-Arg-TrpIC50 = 1100 nM[7]
Ac-His-DPhe-Arg-Trp-NH2IC50 = 1153 nM[8]
MCL-129IC50 = 12.7 nM[9]
Hoo-Phe-Orn-Pro-hle-Pff-Phe-NH2IC50 = 13000 nM[10]
c[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2IC50 = 150 nM[6]
c[Nle-Nle-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 16 nM[6]
c[Nle-Asp-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 170 nM[6]
c[Nle-His-D-Phe-Arg-Trp-Glu]-NH2IC50 = 170 nM[6]
c[Nle-Val-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 180 nM[6]
Alpha-MSHIC50 = 19 nM[11]
c[Thr-Tyr-Thr-His-DNaf-Arg-Trp-Thr-Ile-Pro]IC50 = 22 nM[12]
c[Nle-Val-D-Phe-Arg-Trp-Glu]-NH2IC50 = 2500 nM[6]
c[Nle-Arg-D-Phe-Arg-Trp-Glu]-NH2IC50 = 270 nM[6]
c[Nle-Pro-D-Phe-Arg-Trp-Glu]-NH2IC50 = 2700 nM[6]
c[CO-(CH2)2-CO-Nle-D-Nal(2)-Arg-Trp-Lys]-NH2IC50 = 300 nM[5]
Ac-Nle-c[Asp-His-DNaI(2')-Pro-Trp-Lys]-NH2IC50 = 33 nM[4]
c[CO-(CH2)3-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2IC50 = 330 nM[5]
c[Nle-Glu-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 34 nM[6]
Ac-Phe-[Orn-Pro-cha-Trp-Arg]IC50 = 400 nM[10]
c[CO-o-C6H4-CO-Pro-D-Nal(2)-Arg-Trp-Lys]-NH2IC50 = 430 nM[5]
Ser-Tyr-Ser-Nle-Glu-His-Dphe-ArgIC50 = 5.9 nM[7]
c[Nle-Nle-D-Phe-Arg-Trp-Glu]-NH2IC50 = 600 nM[6]
c[Nle-Gln-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 65 nM[6]
ML-253764IC50 = 708 nM[12]
c[Nle-Arg-D-Nal(2')-Arg-Trp-Glu]-NH2IC50 = 77 nM[6]
c[CO-o-C6H4-CO-Pro-D-Phe-Arg-Trp-Lys]-NH2IC50 = 777 nM[5]
c[CO-(CH2)2-CO-Nle-D-Phe-Arg-Trp-Lys]-NH2IC50 = 930 nM[5]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-oneKi < 1000 nM[13]
Ac-YR[CEH(pCl-dF)RWC]-NH2Ki = 0.14 nM[14]
Ac-YRMEHdFRWGSPPKD-NH2Ki = 0.27 nM[14]
Ac-YR[CEH(pF-dF)RWC]-NH2Ki = 0.28 nM[14]
Ac-YR[CEH(d-2alpha-Nal)RWC]-NH2Ki = 0.3 nM[14]
NDP-SYSMEHFRWGKPVGKi = 0.31 nM[14]
Ac-R[CEHdFRWC]-NH2Ki = 0.44 nM[14]
NDP-alpha-MSHKi = 0.47 nM[15]
Ac-YR[CEHdFRWC]SPPKD-NH2Ki = 0.52 nM[14]
Ac-YRMEHdFRWG-NH2Ki = 0.55 nM[14]
Ac-dR[CEHdFRWC]-NH2Ki = 0.55 nM[14]
Ac-YR[CEHdFRWC]-NH2Ki = 0.77 nM[14]
Ac-YK[CEHdFRWC]-NH2Ki = 1.22 nM[14]
Ac-Tyr-D-Phe-Arg-2-Nal-NHCH3Ki = 104 nM[16]
D-Phe-Arg-2-Nal-NHCH3Ki = 1248 nM[17]
D-Phe-Arg-2-Nal-NHCH3Ki = 1248 nM[16]
Ac-YRC(Me)*EHdFRWC(Me)NH2Ki = 13.25 nM[14]
c[Ser-Tyr-Thr-His-Dphe-Arg-Trp-Thr-Ile-Pro]Ki = 173 nM[12]
MK-10Ki = 190 nM[18]
Ac-[CEHdFRWC]-NH2Ki = 2.29 nM[14]
Ac-YCit[CEHdFRWC]-NH2Ki = 2.54 nM[14]
1-Benzyl-4-methyl-piperazineKi = 2000 nM[19]
Tic-D-Phe-Arg-2-Nal-NHCH3Ki = 24 nM[20]
c(his-D-phe-arg-trp-Ahp)Ki = 244 nM[21]
Ac-His-D-Phe-Arg-2-Nal-NHCH3Ki = 29 nM[16]
Ac-YR[CEHFRWC]-NH2Ki = 30.51 nM[14]
c(his-D-phe-arg-trp-Aoc)Ki = 319 nM[21]
c(his-L-phe-arg-trp-Aoc)Ki = 4420 nM[21]
GPYRMEHFRWGSPPKD-NH2Ki = 5.28 nM[14]
c(his-D-phe-arg-trp-Abu)Ki = 5780 nM[21]
Ac-YR[CE(1-Me-H)dFRWC]-NH2Ki = 6.6 nM[14]
MK-11Ki = 630 nM[18]
c(his-D-phe-arg-trp-Ahx)Ki = 670 nM[21]
1-Methyl-4-(1-phenyl-ethyl)-piperazineKi = 700 nM[19]
AEKKDEGPYRMEHFRWGSPPKDKi = 8.18 nM[14]
Action against Disease ModelBremelanotideBremelanotide 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[22]
The Effect of Target Knockout, Knockdown or Genetic VariationsIncreased food intake, weight and body fat[23]
Ref 1Nat Rev Drug Discov. 2008 Apr;7(4):307-23.Targeting melanocortin receptors: an approach to treat weight disorders and sexual dysfunction. To Reference
Ref 2Curr Top Med Chem. 2006;6(11):1193-203.Discovery and development of pyrazole-scaffold Hsp90 inhibitors. To Reference
Ref 3Curr Top Med Chem. 2006;6(11):1173-82.Geldanamycin, radicicol, and chimeric inhibitors of the Hsp90 N-terminal ATP binding site. To Reference
Ref 4J 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. To Reference
Ref 5J 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. To Reference
Ref 6J Med Chem. 2006 Mar 23;49(6):1946-52.Development of cyclic gamma-MSH analogues with selective hMC3R agonist and hMC3R/hMC5R antagonist activities. To Reference
Ref 7Bioorg Med Chem Lett. 2007 Jun 15;17(12):3310-3. Epub 2007 Apr 6.Squalene-derived flexible linkers for bioactive peptides. To Reference
Ref 8J Med Chem. 1997 Jul 4;40(14):2133-9.Discovery of prototype peptidomimetic agonists at the human melanocortin receptors MC1R and MC4R. To Reference
Ref 9Bioorg 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. To Reference
Ref 10Bioorg 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 vivo activity. To Reference
Ref 11Bioorg 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. To Reference
Ref 12J 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. To Reference
Ref 13J 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. To Reference
Ref 14J Med Chem. 2005 May 5;48(9):3095-8.Discovery of a beta-MSH-derived MC-4R selective agonist. To Reference
Ref 15J 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. To Reference
Ref 16Bioorg 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. To Reference
Ref 17J Med Chem. 2006 Jul 27;49(15):4745-61.Design, synthesis, and evaluation of proline and pyrrolidine based melanocortin receptor agonists. A conformationally restricted dipeptide mimic approach. To Reference
Ref 18J 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. To Reference
Ref 19Bioorg Med Chem Lett. 2005 Nov 15;15(22):4973-8.Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives. To Reference
Ref 20Bioorg 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. To Reference
Ref 21Bioorg 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. To Reference
Ref 22J Sex Med. 2007 Nov;4 Suppl 4:269-79.Bremelanotide: an overview of preclinical CNS effects on female sexual function. To Reference
Ref 23Obes Rev. 2006 Feb;7(1):89-108.Obesity drugs and their targets: correlation of mouse knockout phenotypes with drug effects in vivo. To Reference



 

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Professor in Department of Pharmacy
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