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. Author manuscript; available in PMC: 2016 Mar 6.
Published in final edited form as: Eur J Med Chem. 2014 Dec 19;92:64–77. doi: 10.1016/j.ejmech.2014.12.033

Table 1.

Opioid and NK1 Receptor Affinity and Activity of all Parent and Hybrid Compounds

Compound Number Compound pA2a (NK1R) hNK1Rb (Ki nM) GPIc (IC50 nM) MVDc (IC50 nM) MORc (Ki nM) DORc (Ki nM) Selectivity Ki DOR/Ki MOR
4 H-Dmt-D-Arg-Aba-Gly-NMe-3’,5’-(CF3)2-Bn 7.80 0.50 8.51 43.3 0.42 10.4 25.0
6 Ac-Aba-Gly-NMe-3’,5’-(CF3)2-Bn 8.40 27.0 nd nd nd nd nd
7 H-Dmt-D-Arg-Aba-Gly-NH2 nd nd 0.32 0.42 0.15 0.60 4.0
21 H-Dmt-D-Arg-Aba-β-Ala-NMe-3’,5’-(CF3)2-Bn 6.04 59.7 11.3 6.20 0.08 2.14 25.3
22 H-Dmt-D-Arg-Aba-β-Ala-NMe-Bn 6.44 13.0 1.86 2.16 0.08 0.28 3.5
23 H-Dmt-D-Cit-Aba-β-Ala-NMe-3’,5’-(CF3)2-Bn 6.27 34.7 2.03 1.06 0.37 0.55 1.5
24 H-Dmt-D-Cit-Aba-β-Ala-NMe-Bn nd 3000 0.96 0.33 0.28 0.48 1.7
25 H-Dmt-D-Arg-Aba-Gly-NMe-Bn nd 1530 5.97 8.64 0.09 2.35 24.8
26 H-Dmt-D-Arg-Aba-Gly-NH-Bn nd 6190 4.44 3.50 0.14 0.62 4.4
27 H-Dmt-D-Arg-Aba-Gly-NiBu-3’,5’-(CF3)2-Bn nd 35 19.7 d 14.5 nd nd nd
28 H-Dmt-D-Arg-Aba-Gly-NiBu-Bn nd 1020 P.A e 28.7 nd nd nd
29 H-Dmt-D-Arg-Aba-β-Ala-NiBu-3’,5’-(CF3)2-Bn nd 743 nd nd nd nd nd
30 H-Dmt-D-Arg-Aba-β-Ala-NiBu-Bn nd 308 nd nd nd nd nd
31 H-Dmt-D-Arg-Phe-Sar-NMe-3’,5’-(CF3)2-Bn nd 734 2.95 2.31 0.62 1.7 2.7
32 H-Dmt-D-Arg-Phe-Sar-NMe-Bn nd 16050 3.10 7.76 0.10 4.43 43.4
33 H-Dmt-D-Arg-Aba-β-Ala-NH2 nd nd 0.80 0.24 1.34 17.0 12.7
a

The pA2 values were calculated using Schild's equation.40

b

Inhibitory constants (Ki) of NK1 receptor ligands, measured for the receptor prototype [3H]-SP in the presence of hNK1-CHO membranes. Results are means of three independent experiments. Binding data were calculated using the nonlinear regression/one site competition fitting options of the GraphPad Prism Software.

c

Values represent means of 3-4 experiments. The GPI functional assay is representative of MOR activation, whereas the MVD is a DOR receptor-representative assay. Binding affinities of compounds for MOR and DOR opioid receptors were determined by displacement of [3H]DAMGO ([D-Ala2,NMePhe4,Gly-ol5]enkephalin) and [3H]DSLET ([D-Ser2,Leu5]enkephalin-Thr6) from rat brain membrane binding sites, respectively.

d

partial agonist, Ke = 12,7 nM (μ antagonist)

e

Ke = 5,91 nM (μ antagonist); nd: not determined.