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Table 1 Evaluation of functional activity at MORs using Eurofins DiscoverX HitHunter® cAMP Assay

From: Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent

      
Cmpd R1 R2 R3 R4 LogPa CNS MPOa MOR antagonism
IC50 (nM)b,c
(Imax)d
MOR agonism
EC50 (nM)b
(% efficacy)e
Fentanyl      3.82 4.17 NT 0.22 ± 0.04 (103.35 ± 0.28)
Morphine      0.90 4.94 NT 5.92 ± 0.95 (103.00 ± 0.56)
Oxycodone CH3 =O OH OH 1.03 5.45 NT 102.12 ± 51.64 (105.78 ± 0.51)
Naloxone (4a) Allyl =O OH OH 1.48 5.31 51.16 ± 13.42 (120.11 ± 4.02) 3.15 ± 0.48 (22.36 ± 5.56)
Naltrexone (4b) CPM =O OH OH 1.27 4.83 8.82 ± 1.53 (102.69 ± 0.94) 2.14 ± 1.20 (29.61 ± 6.40)
β-FNA CPM NHCOCH=CHCO2Me, H OH OH 1.08 3.13 31.02 ± 8.34 (59.98 ± 9.42) NT
CCAM CPM =O NHCOCH=CH(4-ClC6H4) OH 3.99 3.17 29.57 ± 2.98 (137.69 ± 5.98)  > 10,000
7 CPM =O OH OCH3 1.82 5.09 > 10,000 103.02 ± 50.94 (45.87 ± 8.62)
8 CPM =O OH H 1.97 5.03 > 10,000 138.63 ± 55.18 (27.42 ± 5.41)
9 CPM =O H OH 2.07 5.03 1.51 ± 0.68 (50.23 ± 4.32) 0.27 ± 0.06 (71.33 ± 4.16)
10 CPM =O OCOCH=CH(4-ClC6H4) OH 4.95 2.54 > 10,000 386.90 ± 115.16 (68.74 ± 8.13)
11 CPM =O OCOCH=CH(4-CH3C6H4) OH 4.85 2.74 > 10,000 168.35 ± 31.99 (68.88 ± 11.09)
12 CPM =O OCOCH=CHC6H5 OH 4.34 3.35 > 10,000 6.60 ± 0.50 (89.14 ± 3.45)
13 CPM =O OCOCH2CH2C6H5 OH 4.05 3.64 > 10,000 16.68 ± 1.60 (78.98 ± 3.84)
14 CPM =O OCOCH2CH3 OH 2.47 5.12 4.22 ± 1.13 (115.18 ± 2.54) 4.98 ± 2.16 (19.63 ± 5.24)
15 CPM =O OCH2CH2CH2Ph OH 4.34 3.44 > 10,000 0.38 ± 0.11 (101.01 ± 1.86)
16 CPM =O OCH2CH2CH2Cy OH 4.81 2.93 > 10,000 1.89 ± 0.61 (98.55 ± 3.8)
17 CPM =O OCH3 OH 1.89 5.12 13.26 ± 6.29 (71.74 ± 12.10) 2.99 ± 1.56 (25.31 ± 2.76)
18 CPM =O OCH2Ph OH 3.61 4.31 38.95 ± 15.76 (102.54 ± 26.42) 15.38 ± 3.52 (19.98 ± 1.1)
19 CPM =O OCH2CH3 OH 2.23 5.04 3.97 ± 1.65 (89.24 ± 5.87) 0.44 ± 0.22 (49.66 ± 8.51)
20 CPM =O OCH2CH2CH3 OH 2.76 4.95 2.55 ± 0.94 (94.95 ± 15.00) 6.57 ± 3.03 (38.72 ± 8.31)
21 CPM =O OCH2CH=CH2 OH 2.60 4.95 2.58 ± 0.75 (96.84 ± 5.49) 0.72 ± 0.33 (37.41 ± 8.47)
22 CPM =O (R)-OCH2CHOHCH2OH OH 0.60 3.79 6.49 ± 1.49 (149.78 ± 15.31) > 10,000
5 CPM =CH2 OH OH 1.95 4.72 2.13 ± 0.20 (128.85 ± 7.09) > 10,000
23 CPM α-OH, H OH OH 0.84 4.43 20.83 ± 9.92 (69.00 ± 9.72) 2.22 ± 1.04 (49.31 ± 11.57)
24 CPM β-OH, H OH OH 0.84 4.43 5.85 ± 2.03 (110.63 ± 6.30) 0.94 ± 0.35 (26.88 ± 4.74)
25 CPM α-OCH3, H OH OH 1.49 4.77 18.59 ± 5.87 (85.54 ± 5.14) 1.86 ± 0.39 (58.16 ± 4.45)
26 CPM β-OCH3, H OH OH 1.49 4.77 4.52 ± 1.62 (99.67 ± 7.40) 0.88 ± 0.43 (39.02 ± 5.62)
27 CPM H2 OH OH 1.86 4.71 8.83 ± 3.52 (121.83 ± 5.64) 0.88 ± 0.43 (31.69 ± 3.69)
28 CPM =CH2 OCH2CH=CH2 OH 3.80 4.71 2.03 ± 0.96 (100.42 ± 18.87) 0.34 ± 0.15 (38.30 ± 7.02)
29 CPM =CH2 OCH2CH2CH3 OH 3.95 4.55 2.06 ± 0.53 (86.70 ± 5.46) 1.21 ± 0.44 (16.99 ± 3.50)
30 CPM =CH2 (R)-OCH2CHOHCH2OH OH 1.75 4.78 3.58 ± 1.28 (115.90 ± 8.44) > 10,000
  1. aCalculated using CDD Vault
  2. bValues are expressed as the mean ± SEM of at least three independent measurements
  3. cAntagonist potency (IC50) determined versus EC90 of fentanyl
  4. dDegree of antagonism (Imax) normalized to 4b
  5. eAgonist efficacy expressed as percent stimulation