TABLE 1

Analysis of the SAR for [d-Arg1,d-Phe5,d-Trp7,9, Leu11]substance P on the ghrelin receptor with respect to inverse agonist potency (i.e., EC50) for inhibition of the constitutive stimulation of inositol phosphate accumulation and affinity (i.e., IC50) in competition binding experiments using [35S]MK677 as radioactive ligand as determined in transiently transfected COS-7 cells

Fmut indicates the -fold shift in potency or affinity induced by the structural change in the ligand compared with the [d-Arg1,d-Phe5,d-Trp7,9, Leu11]substance P peptide.






EC50

n

Fmut

IC50

n

Fmut
nM nM
1 rPKPfQwFwLL-NH2 18 ± 2 11 1.0 3.2 ± 0.7 4 1.0
2 PKPfQwFwLL-NH2 25 ± 9 5 1.4 2.2 ± 0.4 3 0.7
3 KPfQwFwLL-NH2 44 ± 3 4 2.4 17.0 ± 3 3 5.3
4 PfQwFwLL-NH2 61 ± 23 3 3.4 >1000.0 4 >310
5 fQwFwLL-NH2 29 ± 9 8 1.6 17.0 ± 4 3 5.3
6 QwFwLL-NH2 990 ± 90 4 55.0 120.0 ± 30 4 38.0
7 wFwLL-NH2 >1000a 5»55.0 530.0 ± 230 4 170.0
8 rPKPAQwFwLL-NH2 350 ± 50 3 19.0 68.0 ± 20 3 21.0
9 rPKPfAwFwLL-NH2 32 ± 1 3 1.8 10.0 ± 3 3 3.1
10 rPKPfQAFwLL-NH2 >1000 3 >55.0 >1000 3 >310
11 rPKPfQwAwLL-NH2 310 ± 40 3 17.0 64.0 ± 5 3 20.0
12 rPKPfQwFALL-NH2 >1000 3 >55.0 >1000 3 >310
13 rPKPfQwFwAL-NH2 >1000 3 >55.0 110.0 ± 40 3 34.0
14 rPKPfQwFwLA-NH2 31 ± 6 3 1.7 19.0 ± 3 4 5.9
15 rPKPfQWFwLL-NH2 210 ± 6 3 12.0 97.0 ± 25 3 30.0
16 rPKPfQwFWLL-NH2 >1000 3 >55.0 150.0 ± 19 3 47.0
17 rPKPFQwFwLL-NH2 23 ± 5 4 1.3 4.3 ± 0.5 3 1.3
18 rPKPyQwFwLL-NH2 12 ± 3 4 0.7 3.9 ± 1.8 3 1.2
19 rPKPwQwFwLL-NH2 11 ± 4 3 0.6 11.0 ± 2 3 3.4
20 rPKP QwFwLL-NH2 52 ± 14 4 2.9 26.0 ± 3.5 3 8.1
21 KPfQwFwL -NH2 >1000 3 >55.0 38.0 ± 13 3 12.0
22
KPfQwFw -NH2
>1000
3
>55.0
150.0 ± 30
3
47.0
  • a The dose-responds curve is biphasic, composed of a partial agonist component at 10 nM concentration and after partial inverse agonism.