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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