Table 4.
Selective hMC4R antagonists.
| No. | Sequence | hMC1R
|
hMC3R
|
hMC4R
|
hMC5R
|
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| IC50, nM |
EC50, nM |
% Max effect |
IC50, nM |
EC50, nM |
% Max effect |
IC50, nM |
EC50, nM |
% Max effect |
IC50, nM |
EC50, nM |
% Max effect |
||
| MT-II | Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 | 0.2 | 0.3 | 100 | 1.25 | 1.85 | 100 | 1.07 | 2.87 | 100 | 7.47 | 3.3 | 100 |
| SHU-9119 | Ac-Nle-c[Asp-His-D-Nal(2′)-Arg-Trp-Lys]-NH2 | 0.2 | 0.3 | 100 | 1.9 | NA | 0 | 1.07 | 2 | 0 | 3 | 3.3 | 97 |
| 15 | Cyclo(6β-10(ε)-(succinyl6-D-Nal(2′)-Arg-Trp-Lys) NH2 | ND | ND | ND | Ki 150 | NA | 0 | 0.5 | NA | 0 | Ki 540 | 530 | ND |
| 16 | Ac-c[Cys-Nle-Arg-His-D-Nal(2prime;)-Arg-Trp-Gly-Cys-NH2 | Ki 18.6 | NA | NA | Ki 5.45 | NA | NA | Ki 0.29 | NA | NA | Ki 3.29 | NA | NA |
| 17 | H-Tyr-Val-Nle-Glu-His-Phe-Arg-D-Nal(2′)-Asp-Arg-Phe-Gly-NH2 | ND | ND | ND | Ki 15 | 2400 | 31 | Ki 1.5 | > 10,000 | NA | Ki 17 | 28 | 80 |
| 18 | H-Tyr-Val-c[Pen-Gly-His-Phe-Arg-Trp-Cys]-Arg-Phe-Gly-NH2 | ND | ND | ND | Ki 150 | 400 | 77 | Ki 12 | > 10,000 | NA | Ki 1700 | > 10,000 | NA |
| 19 | c[Nle-Asp-D-Phe-Arg-Trp-Glu]-NH2 | > 10,000 | NA | 0 | > 10,000 | NA | 0 | 150 | NA | 0 | > 10,000 | NA | 0 |
| 20 | Ac-c[Cys-Glu-His-D-Nal(2′)-Arg-Trp-Gly-Cys]-Pro-Pro-Lys-Asp-NH2 | Ki 108 | ND | ND | Ki 54 | - | 0 | Ki 3.16 | - | 0 | Ki 694 | - | - |
| 21 | Ac-c[Cys-Glu-His-diCl-D-Phe-Arg-Trp-Gly-Cys]-Pro-Pro-Lys-Asp-NH2 | 60.1 | NA | NA | 73.7 | NA | NA | 0.95 | NA | NA | 211 | NA | NA |
| 22 | Ac-Nle-c[Asp-Aic-D-Nal(2′)-Arg-Trp-Lys]-NH2 | ND | ND | ND | 190 | NA | 0 | 1.3 | NA | 0 | 12 | 17 | 73 |
| 23 | Ac-Nle-c[Asp-Cpe-D-Nal(2′)-Arg-Trp-Lys]-NH2 | ND | ND | ND | 110 | NA | 0 | 0.51 | NA | 0 | 16 | 45 | 79 |
| 24 | Ac-DNal(2′)-Arg-Nal(2′)-NH2 | NB | - | - | NB | - | - | 11.6 | NA | 0 | NB | - | - |
| 25 | Ac-c[Cys-His-D-Phe-Nα-guanidinylbutyl-Cys]-Trp-NH2 | NB | - | - | NB | - | - | 1.8 | NA | NB | - | - | |
| 26 | Ac-c[Cys-His-D-Phe-Cys]-Nα-guanidinylbutyl-D-Trp-NH2 | NB | - | - | > 1000 | - | - | 0.7 | > 1000 | 18 | NB | - | - |
| MT-II | Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 | 0.2 ± 0.01 | 0.3 ± 0.04 | 100 | 1.25 ± 0.2 | 1.85 ± 0.2 | 100 | 1.07 ± 0.3 | 2.87 ± 0.52 | 100 | 7.47 ± 0.23 | 3.3 ± 0.7 | 100 |
| SHU-9119 | Ac-Nle-c[Asp-His-N-NAL(2′)-Arg-Trp-Lys]-NH2 | 0.2 ± 0.01 | 0.3 ± 0.04 | 100 | 1.9 ± 0.2 | NA | 0 | 1.07 ± 0.3 | 2 ± 0.2 | 0 | 3 ± 0.3 | 3.3 ± 0.7 | 97 |
| 27 | 1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiper adin-1-yl)ethyl]-4-[4(2-methoxynaphthalen-1-yl) butyl]piperazine | NB | - | - | NB | - | - | Ki 7.6 | NA | 0 | ND | ND | ND |
| 28 | (1-[2-(4-Fluorophenyl)-2-(4-methylpiperazin-1-yl)ethyl]-4-[4-(1-naphthyl)butyl]piperazine | > 10,000 | - | - | > 10,000 | - | - | 124 | 5100 | 0 | > 10,000 | - | - |
| 29 | Pyrrolidine derivatives, Figure 1 | 140 | ND | ND | 1400 | ND | ND | 8.6 | NA | 0 | 380 | ND | ND |
| 30 | Structure Figure 1 | ND | ND | ND | ND | ND | ND | 330 | NA | 0 | ND | ND | ND |
| 31 | Structure Figure 1 | ND | ND | ND | ND | ND | ND | 160 | NA | 0 | ND | ND | ND |
| 32 | Structure Figure 1 | 111 | NA | - | 46 | NA | - | 1 | NA | 0 | 26 | NA | - |
| 33 | Structure Figure 1 | 5700 | NA | NA | 1100 | NA | NA | 4.2/2.8* | NA | NA | 540 | NA | NA |
| 34 | Structure Figure 1 | NA | NA | NA | Ki 640 | NA | NA | Ki 1.8 | NA | NA | NA | NA | NA |
| 35 | Structure Figure 1 | ND | ND | ND | 790 | NA | - | Ki 3.2 | NA | 0 | ND | ND | ND |
IC50 = Concentration of peptide at 50% specific binding (n = 4). EC50 = Effective concentration of peptide that was able to generate 50% maximal intracellular cAMP accumulation (n = 4). % Max effect = % of cAMP produced at 10 μM ligand concentration in relation to MT-II. NA = 0% cAMP accumulation observed at 10 μM. The peptides were tested at a range of concentration from 10−10 to 10−5 M. ND: Not determined.
The antagonist properties of the lead compounds were evaluated by their ability to competitively displace the MT-II agonist in a dose-dependent manner, at up to 10 μM. The pA2 values were obtained using the Schild analysis method.
Two radioisotopes were used ([125I]NDP-α-MSH and [125I]AGRP).
NA: No activity at 10−5 M; NB: No binding at 10−5 M.