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. 2017 Aug 21;60(17):7579–7590. doi: 10.1021/acs.jmedchem.7b00981

Table 1. Binding Affinities and Functional Activities at the Human Opioid Receptors and Calculated Physicochemical Properties of New Diphenethylamines 3–22 and Reference Compounds 1 and 2.

  receptor binding (Ki, nM)a
 functional activityb
    
  affinity
 selectivity
 [35S]GTPγS KOP
 physicochemical propertiesc
compd KOP MOP DOP MOP/KOP DOP/KOP EC50 or Ke (nM) % stim clogP clogD7.4
1d 0.49 ± 0.20 542 ± 239 >10000 1106 >20000 3.62 ± 1.87 90.0 ± 3.7 5.04 2.04
2d 5.90 ± 3.00 826 ± 98 >10000 140 >1700 35.0 ± 5.3 53.4 ± 8.1 4.64 1.73
3 0.017 ± 0.002 274 ± 20 2268 ± 625 16118 133471 3.87 ± 1.44 82.8 ± 3.7 5.43 2.34
4 0.061 ± 0.027 537 ± 172 2139 ± 346 8803 35066 0.23 ± 0.08 61.9 ± 8.1 5.83 2.73
5 0.71 ± 0.25 463 ± 95 1862 ± 501 652 2623 4.65 ± 1.63 79.5 ± 9.8 5.71 3.16
6 10.3 ± 1.2 670 ± 174 3539 ± 38 65 344 46.1 ± 13.9 50.7 ± 5.0 4.72 1.96
7 2.69 ± 0.43 259 ± 86 2743 ± 677 96 1020 22.1 ± 3.1 74.7 ± 3.6 5.47 2.61
8 0.38 ± 0.09 230 ± 43 3340 ± 844 605 8789 4.44 ± 1.36 71.1 ± 5.2 4.75 1.81
9 4.62 ± 0.11 631 ± 215 2850 ± 720 137 617 20.6 ± 0.6 51.3 ± 7.6 4.35 1.51
10 19.1 ± 0.6 358 ± 28 738 ± 16 19 39 154 ± 62 37.5 ± 0.6 4.39 2.49
11 0.14 ± 0.04 167 ± 52 1432 ± 506 1193 10229 17.6 ± 7.1 91.1 ± 3.6 5.54 2.50
12 0.31 ± 0.04 584 ± 119 2775 ± 545 1884 8952 13.7 ± 3.5 80.4 ± 5.8 5.15 2.11
13 2.10 ± 0.26 211 ± 17 1469 ± 147 100 699 16.6 ± 0.7 65.6 ± 3.4 5.18 2.39
14 3.43 ± 0.75 16.1 ± 4.7 428 ± 93 5 125 22.2 ± 3.6 76.4 ± 1.1 4.75 1.77
15 1.85 ± 0.07 234 ± 112 1637 ± 557 126 885 22.2 ± 7.2 84.3 ± 2.7 5.54 2.46
16 43.5 ± 1.5 192 ± 17 1099 ± 485 4 25 248 ± 89 29.8 ± 3.4 4.39 2.44
17 3.56 ± 0.94 460 ± 127 >10000 129 >2800 24.3 ± 1.5e   4.35 1.46
18 0.072 ± 0.027 398 ± 57 >10000 5529 >138000 6.90 ± 3.35 66.1 ± 10.6 5.17 2.56
19 0.040 ± 0.006 851 ± 292 >10000 21275 >250000 2.77 ± 0.29 88.9 ± 4.6 5.97 3.28
20 0.12 ± 0.01 557 ± 198 >10000 4642 >83000 1.49 ± 0.04 57.5 ± 4.4 4.89 2.32
21 3.37 ± 1.54 523 ± 33 1312 ± 281 155 389 36.7 ± 14.0 69.1 ± 1.9 4.89 2.29
22 79.1 ± 12.5 1065 ± 263 2178 ± 881 13 28 359 ± 116 91.9 ± 4.7 5.32 2.26
a

Determined in competition binding assays using CHO cell membranes stably expressing human opioid receptors (CHO-hKOP, CHO-hMOP, or CHO-hDOP cells).

b

Determined in the [35S]GTPγS binding assay using CHO-hKOP cell membranes. Percentage stimulation (% stim) relative to the KOP full agonist U69,593.

c

Calculated log P (clogP) and calculated log D at pH 7.4 (clogD7.4) using MarvinSketch 17.10 (ChemAxon).

d

Data from ref (9a).

e

Antagonist Ke value at the KOP receptor against U69,593 determined in the [35S]GTPγS binding assay. Values are means ± SEM of at least three independent experiments.