Among therapeutically valuable opioids, morphinans are of the utmost clinical importance as analgesic drugs because of their agonistic actions to the mu-opioid receptor. They include powerful pain relieving agents, such as naturally occurring alkaloids (e.g., morphine and codeine), semisynthetic analogues (e.g., hydrocodone, hydromorphone, oxycodone, oxymorphone and buprenorphine), and synthetic derivatives (e.g., levorphanol).
Compound | Agonist Potencies IC50 × 108 (M) a | Antinociceptive Potencies ED50 b |
---|---|---|
a | 14.4 | 0.27 nmol/mouse, i.c.v. 9.8 µmol/kg, i.v. 30.3 µmol/kg, p.o. |
b | 13.0 | - c |
c | 3.9 | 0.17 nmol/mouse, i.c.v. 11 µmol/kg, i.v. ~20 µmol/kg, p.o. |
d | 2.7 | 0.25 nmol/mouse, i.c.v. <20 µmol/kg, i.v. >25 µmol/kg, p.o. |
e | 3.1 | 0.44 nmol/mouse, i.c.v. <0 µmol/kg, i.v. |
Morphine | 6053 | 437 | 1613 | 1472 | |
Fentanyl | 38.6 | ||||
14-OMO (1) | 14.9 | 3.26 | |||
HS-730 (2a) | α-Gly | 58.5 | 35.7 | 72 | 110 |
HS-731 (2b) | β-Gly | 29.0 | 27.5 | 125 | 204 |
HS-935 (3a) | α-L-Ala | 68.9 | 16.0 | ||
HS-936 (3b) | β-L-Ala | 53.4 | 86.3 | ||
HS-937 (4a) | α-L-Phe | 315 | 31.1 | 171 | 292 |
HS-938 (4b) | β-L-Phe | >3600 | 579 | 79 | 107 |
19a | |||||
α-β-Ala | |||||
31.2 | |||||
20a | α-GABA | 41.9 | |||
21a | β-L-Val-L-Tyr | 178 | |||
22a | β-Gly-Gly | 104 | |||
24a | α-Gly | 81.1 | |||
24b | β-Gly | 130 |
Pain Model | Route | ED50 | Reference |
---|---|---|---|
Acute nociception Radiant heat tail-flick test (rat) |
i.c.v. s.c. |
0.030 nmol/rat 29.0 nmol/kg |
[40] [40] |
Trigeminal nociception Eye wiping test (mouse) |
i.p. |
50 µg/kg a |
[43] |
Compound | Pain Model (Species) | ED50 (Systemic Administration) | ED50 (Central Administration) | Reference |
---|
Compound | Pain Model (Species) | ED50 Ratio Peripheral/Central Administration |
Reference | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Morphine | hot-plate test (mouse) | 4.5 mg/kg, s.c. | ||||||||||
Fentanyl | radiant heat tail-flick test (rat) | 23 | [50] | |||||||||
[ | 50 | ] | hot water tail-flick test (rat) | 3.41 mg/kg, i.p. | [64] | Visceral pain | ||||||
Morphine | radiant heat tail-flick test (rat) | 172 | [40] | |||||||||
radiant heat tail-flick test (mouse) | 5.5 nmol/mouse, i.c.v. | [59] | ||||||||||
159 | [58] | Acetic-acid-induced writhing assay (mouse) | i.c.v. s.c. |
0.49 pmol/mouse 51 nmol/kg |
[ | radiant heat tail-flick test (mouse)42 | 314 ng/mouse, i.c.v. | |||||
125 | [53] | ] | [52[42] |
|||||||||
] | s.c. | 27.5 µg/kg | ||||||||||
[ | radiant heat tail-flick test (rat) | 6221 nmol/kg, s.c. | 36 | 38.6 nmol/rat, i.c.v] | ||||||||
[ | 58 | ] | ||||||||||
acetic-acid-induced writhing assay (rat) | 118 | [61] | Inflammatory pain Formalin test (rat) Carrageenan-induced thermal and mechanical hyperalgesia (rat) |
i.pl. s.c. s.c. p.o. |
Phase I: 0.2 nmol; Phase II: 0.4 nmol Phase I: 125 nmol/kg; Phase II: 204 nmol/kg 20 µg/kg a 10 mg/kg a |
[44] [40] [41] [ |
5a | α-L-Ser | 32.1 | |||
6b | β-L-Val | 117 | ||||||||||
7a | α-L-Lys | 20.6 | ||||||||||
41 | ] | 8a | α-L-Tyr | 14.6 | ||||||||
9b | β-L-Trp | 92.7 | ||||||||||
10a | α-L-Asn | 15.2 | ||||||||||
12a | α-L-Asp | 38.2 | ||||||||||
13a | α-L-Glu | 36.1 | ||||||||||
15b | β-D-Val | |||||||||||
Neuropathic pain, sciatic nerve ligation—Mechanical hyperalgesia (rat) | i.pl. | 441 nmol | [44 | 14.0 | ||||||||
] | 16a | α-D-Phe | 18.1 | |||||||||
16b | β-D-Phe | 250 | ||||||||||
17a | α-L-Chg | 20.6 |
Compound | R | Opioid Receptor Binding a | Agonist Activity | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Compound | b | R | clogD | Opioid Receptor Binding, Ki (nM) a | clogD7.4 b7.4 c | ||||||||
MOR Ki (nM) |
DOR Ki | ||||||||||||
MOR | (nM) | DORKOR Ki (nM) |
Ki Ratio MOR/DOR/KOR |
MOR EC50 (nM) |
KORMOR % stim. |
Ki Ratio MOR/DOR/KORDOR EC50 (nM) |
DOR % stim. |
radiant heat tail-flick test (rat) | |||||||||||||||||
2.68 mg/kg, i.p. | |||||||||||||||||
3.51 µg/rat, i.t. | |||||||||||||||||
[ | 60 | ] | |||||||||||||||
M6SU | radiant heat tail-flick test (rat) | 25,493 | [58] | radiant heat tail-flick test (rat) | 9.1 mg/kg, p.o. | [60] | |||||||||||
acetic-acid-induced writhing assay (mouse) | 221,444 | [62] | acetic-acid-induced writhing assay (mouse) | ||||||||||||||
14-O | 238.6 nmol/kg, i.p. | 2.02 nmol/mouse, i.c.v. | -MeM6SU | radiant heat tail-flick test (rat) | 11,615[61] | ||||||||||||
[ | 58 | ] | formalin-induced inflammatory pain (rat) | Phase II: 0.259 mg/kg, i.p. | |||||||||||||
acetic-acid-induced writhing assay (mouse) | [ | 61] | |||||||||||||||
51,177 | [ | 62] | formalin-induced inflammatory pain (rat) | Phase I and II: 3884, 7769, 15,538, 31,075 nmol/kg, s.c. a | |||||||||||||
14-O | [ | 65 | ] | ||||||||||||||
-MeC6SU | radiant heat tail-flick test (rat) | 314 | [53] | neuropathic pain, CCI (rat) hyperalgesia allodynia |
2.65 mg/kg, i.p. 1.45 mg/kg, i.p. |
[60] | |||||||||||
STZ-induced diabetic neuropathic pain— tail withdrawal test (rat) |
6.47 mg/kg, i.p. | [63] | |||||||||||||||
STZ-induced diabetic neuropathic pain— paw withdrawal test (rat) |
40,000 nmol/kg, s.c. a | [66] | |||||||||||||||
Codeine | radiant heat tail-flick test (rat) | 54.01 µmol/kg | [53] | ||||||||||||||
M6SU | hot-plate test (mouse) | 1.7 mg/kg, s.c. | [50] | ||||||||||||||
hot water tail-flick (rat) | 0.82 mg/kg, i.p. | [63] | |||||||||||||||
radiant heat tail-flick test (mouse) | 0.19 nmol/mouse, i.c.v. | [59] | |||||||||||||||
radiant heat tail-flick test (mouse) | 10.6 ng/mouse, i.c.v. | [52] | |||||||||||||||
radiant heat tail-flick test (rat) | 9305 nmol/kg, s.c. | 0.356 nmol/rat, i.c.v. | [58] | ||||||||||||||
radiant heat tail-flick test (rat) | 0.54 mg/kg i.p. | 0.29 μg/rat, i.t. | [60] | ||||||||||||||
radiant heat tail-flick test (rat) | 4.97 mg/kg, p.o. | [60] | |||||||||||||||
paw pressure threshold test (rat) | 2.3 mg/kg, i.p. | [64] | |||||||||||||||
acetic-acid-induced writhing assay (mouse) | 1993 nmol/kg, s.c. | 9 pmol/mouse, i.c.v. | [62] | ||||||||||||||
formalin-induced inflammatory pain (rat) | Phase II: 0.094 mg/kg, i.p. | [60] | |||||||||||||||
CFA-induced inflammatory pain—paw pressure test (rat) | 292 nmol/kg, s.c. | [62] | |||||||||||||||
neuropathic pain, CCI (rat) hyperalgesia allodynia |
0.40 mg/kg, i.p. 0.19 mg/kg, i.p. |
[60] | |||||||||||||||
STZ-induced diabetic neuropathic pain—tail withdrawal test (rat) | 0.35 mg/kg, i.p. | [63] | |||||||||||||||
C6SU | radiant heat tail-flick test (mouse) | 200 ng, i.c.v b | [52] | ||||||||||||||
radiant heat tail-flick test (rat) | weak effect (<20%), s.c. | [53] | |||||||||||||||
CFA-induced inflammatory pain—paw pressure test (rat) | 6.6 and 13.2 µmol/kg, s.c. a | [53] | |||||||||||||||
14-O-MeM6SU | radiant heat tail-flick test (rat) | 182.4 nmol/kg, s.c. | 0.0157 nmol/rat, i.c.v. | [58] | |||||||||||||
acetic-acid-induced writhing assay (mouse) | 87 nmol/kg, s.c. | 1.7 nmol/mouse, i.c.v. | [62] | ||||||||||||||
KOR | |||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
EC | 50 | (nM) | KOR | % stim. | |||||||||||||
14-OMO (1) | 0.10 | 4.80 | 10.2 | 1/48/102 | 3.83 | 97 | 37.3 | 106 | 116 | 77 | 0.48 | ||||||
POMO (23) | 0.073 | 0.13 | 0.30 | 1/1.8/4.1 | 2.89 | ||||||||||||
HS-730 (2a) | α-Gly | 0.89 | 15.4 | 43.2 | 1/7/49 | 1.16 | |||||||||||
Compound | R, Amino Acid Substitution at Position 6 |
Radiant Heat Tail-Flick Test (Rat), ED50 | Ratio ED50 (nmol/kg, s.c.)/ ED50 (nmol/rat, i.c.v.). |
||||||||||||||
s.c. (nmol/kg) | i.c.v. (nmol/rat) | ||||||||||||||||
Morphine | 6053 | 35.1 | 172 | ||||||||||||||
99 | 9.61 | 103 | 399 | 87 | −3.35 | ||||||||||||
24a | |||||||||||||||||
Fentanyl | α-Gly | 0.19 | 38.6 | 1.66 | 23 | HS-731 (2b) | β-Gly | 0.83 | 7.86 | 44.8 | 1/9.5/54 | 3.78 | 98 | ||||
14-OMO ( | 7.92 | 1 | 103 | 361 | ) | 82 | −3.35 | ||||||||||
14.9 | 0.172 | HS-935 (3a) | α-L-Ala | 0.77 | 26.9 | 142 | 1/35/184 | 1.34 | 97 | 9.55 | 93 | 214 | 51 | −2.81 | |||
0.22 | 0.73 | 1/1.2/3.8 | −0.85 | ||||||||||||||
45.6 | |||||||||||||||||
24b | β-Gly | 0.16 | 0.19 | 0.81 | 1/1.2/5.1 | 87−0.85 | |||||||||||
HS-730 (2a) | α-Gly | 58.5 | 0.031 | 1887 | HS-936 (3b) | β-L-Ala | 1.90 | 7.71 | 63.7 | 1/4.1/34 | 6.24 | 87 | 5.20 | 104 | 392 | 64 | |
HS-731 ( | −2.81 | ||||||||||||||||
2b) | β-Gly | 29.0 | 0.030 | 967 | HS-937 (4a) | α-L-Phe | |||||||||||
HS-935 ( | 0.95 | 3a | 3.67 | 28.5 | )1/3.9/30 | 0.38 | 93 | 0.39 | 102 | 219 | 39 | −1.13 | |||||
α-L-Ala | 68.9 | 0.121 | 569 | HS-938 (4b) | β-L-Phe | 2.58 | 1.03 | 151 | 1/0.4/59 | 6.76 | 99 | 0.48 | 94 | 1172 | 81 | ||
HS-936 ( | −1.13 | ||||||||||||||||
3b) | β-L-Ala | 53.4 | 0.082 | 651 | 5a | α-L-Ser | 2.21 | 5.32 | 196 | 1/2.4/89 | 1.60 | 87 | 13.9 | 101 | 1213 | 44 | −3.89 |
HS-937 (4a) | α-L-Phe | 315 | 0.063 | 5000 | 5b | β-L-Ser | 2.14 | 5.29 | 152 | 1/2.5/71 | 3.56 | 101 | |||||
HS-938 (4b | 6.98 | ) | β-L-Phe | 98 | 201 | 88 | −3.89 | ||||||||||
>3600 | 0.776 | >4600 | 6a | α-L-Val | 3.16 | 3.91 | 325 | 1/1.2/103 | 10.5 | 95 | 33.8 | 91 | 462 | 51 | −1.94 | ||
6b | β-L-Val | 3.04 | 3.52 | 305 | 1/1.2/100 | 11.7 | 84 | 5.73 | 96 | 1117 | 24.7 | 93 | 6.23 | 95 | 774 | 60 | −1.41 |
68 | −1.94 | ||||||||||||||||
7a | α-L-Lys | 0.19 | 1.27 | 12.6 | 1/6.7/66 | 2.25 | 9 | 152 | 106 | 118 | 79 | −5.57 | |||||
7b | β-L-Lys | 0.53 | 3.34 | 33.7 | 1/6.3/64 | 6.85 | 90 | 45.1 | 93 | 525 | 62 | −5.57 | |||||
8a | α-L-Tyr | 0.83 | 2.18 | 39.5 | 1/2.6/48 | 1.87 | 92 | 1.76 | 88 | 100 | 62 | −1.41 | |||||
8b | β-L-Tyr | 3.20 | 3.89 | 186 | 1/1.2/58 | 9a | α-L-Trp | 0.36 | 1.02 |
Compound | Opioid Receptor Binding, Ki (nM) a | |||
---|---|---|---|---|
MOR | DOR | KOR | Ki Ratio MOR/DOR/KOR |
|
Morphine | 4.37 | 2951 | 113 |
Compound | MVD Bioassay | [35S]GTPγS Binding Assay | |||||||
---|---|---|---|---|---|---|---|---|---|
EC50 (nM) | Tissue | EC50 (nM) | Emax (%) | ||||||
1/675/26 | |||||||||
Morphine | 347 | Rat brain Guinea-pig brain |
250 462 |
129 | |||||
Codeine | 737 | - b | - | - | |||||
119 | |||||||||
Codeine | >1000 | Rat brain Guinea-pig brain |
- a - |
110 104 |
M6SU | 11.5 | 525 | 275 | 1/46/24 |
M6SU | 103 | Rat brain Guinea-pig brain |
105 - |
133 - |
C6SU | 96.9 | 968 | ||
C6SU | b | - | 1/10/- | ||||||
>1000 | Rat brain | Guinea-pig brain |
>10,000 - |
121 102 |
14-O-MeM6SU | 1.12 | 10.2 | ||
14-O-MeM6SU | 4.38 | Rat brain | 295 | 1/9/263 | |||||
Guinea-pig brain | 19.1 | - |
201 - |
14-O-MeC6SU | 3.37 | 346 | 246 | 1/103/73 |
14- | ||||
O | ||||
-MeC6SU | ||||
238 | Rat brain | Guinea-pig brain |
301 >1000 |
128 130 |
formalin-induced inflammatory pain (rat) | ||||
Phase I: 3506 and 1012 nmol/kg, s.c. | ||||
a | ||||
Phase II: 253, 506 and 1012 nmol/kg, s.c. | ||||
a | ||||
[ | ||||
65 | ||||
] | ||||
CFA-induced inflammatory pain—paw pressure test (rat) | ||||
45 nmol/kg, s.c. | ||||
[ | ||||
62 | ||||
] | ||||
STZ-induced diabetic neuropathic pain—paw withdrawal test (rat) | 253, 506 and 1012 nmol/kg, s.c. a | [66] | ||
14-O-MeC6SU | radiant heat tail-flick test (rat) | 5.34 µmol/kg, s.c. | 0.017 µmol/animal, i.c.v. | [53] |
CFA-induced inflammatory pain—paw pressure test (rat) | 6.1 and 12.2 µmol/kg, s.c. a | [53] |
25.1 | ||||||||||||
1/2.8/70 | ||||||||||||
0.51 | ||||||||||||
93 | ||||||||||||
2.52 | ||||||||||||
102 | ||||||||||||
70.1 | ||||||||||||
61 | ||||||||||||
−1.03 | ||||||||||||
9b | β-L-Trp | 0.65 | 1.19 | 8.66 | 1/1.8/13 | 1.64 | 101 | 2.18 | 96 | 181 | 87 | −1.03 |
10a | α-L-Asn | 1.17 | 3.37 | 74.0 | 1/2.9/63 | 0.83 | 99 | 9.78 | 106 | 81.7 | 67 | −4.29 |
10b | β-L-Asn | 1.26 | 2.25 | 103 | 1/1.8/82 | 2.04 | 96 | 3.18 | 88 | 923 | 71 | −4.29 |
11a | α-L-Gln | 3.24 | 5.13 | 351 | 1/1.6/108 | 2.27 | 90 | 7.80 | 104 | 185 | 70 | −4.04 |
11b | β-L-Gln | 2.48 | 4.87 | 290 | 1/2.0/117 | 9.54 | 98 | 3.96 | 103 | 1410 | 63 | −4.04 |
12a | α-L-Asp | 1.36 | 14.6 | 50.2 | 1/11/37 | 4.10 | 90 | 10.1 | 97 | 2991 | 83 | −5.64 |
12b | β-L-Asp | 3.42 | 22.6 | 351 | 1/6.6/103 | 1.45 | 74 | 11.8 | 101 | 753 | 49 | −5.64 |
13a | α-L-Glu | 1.45 | 9.03 | 87.2 | 1/6.2/60 | 3.11 | 105 | 10.8 | 98 | 1167 | 68 | −5.39 |
13b | β-L-Glu | 11.6 | 7.64 | 1252 | 1/0.7/108 | 12.7 | 98 | 4.60 | 101 | 2233 | 76 | −5.39 |
14a | α-D-Ala | 0.69 | 10.4 | 71.5 | 1/15/104 | 1.44 | 100 | 24.3 | 106 | 254 | 67 | −2.81 |
14b | β-D-Ala | 1.48 | 11.3 | 142 | 1/7.6/96 | 15.4 | 102 | 5.46 | 106 | 1001 | 86 | −2.81 |
15a | α-D-Val | 1.70 | 1.93 | 202 | 1/1.1/119 | 4.51 | 105 | 1.12 | 93 | 2218 | 96 | −1.94 |
15b | β-D-Val | 1.02 | 1.68 | 159 | 1/1.6/156 | 2.38 | 101 | 1.30 | 99 | 1278 | 98 | −1.94 |
16a | α-D-Phe | 0.61 | ||||||||||
1/16/59 | ||||||||||||
2.88 | ||||||||||||
103 | ||||||||||||
34.4 | 103 | 2034 | 104 | −2.93 | ||||||||
20b | β-GABA | 1.41 | 6.61 | 147 | 1/4.7/104 | 12.3 | 86 | 6.06 | 103 | 3396 | 74 | −2.93 |
21a | α-L-Val-L-Tyr | 0.82 | 1.19 | 69.0 | 1/1.5/84 | 0.89 | 84 | 1.16 |
Compound | Amino Acid Substitution at Position 6 |
Radiant Heat Tail-Flick Test (Rat) ED50 (nmol/kg, s.c.) |
Writhing Assay (Mouse) ED50 (µg/kg, s.c.) |
Formalin Test (Rat) ED50 (nmol/kg, s.c.) |
|
---|---|---|---|---|---|
Phase I | Phase II | ||||
18a | |||||
α-L-Abu | |||||
17.5 |
3.69 | ||||||||||||
76.4 | ||||||||||||
1/6.0/125 | ||||||||||||
0.77 | ||||||||||||
96 | ||||||||||||
8.36 | ||||||||||||
95 | ||||||||||||
215 | ||||||||||||
80 | ||||||||||||
−1.13 | ||||||||||||
16b | ||||||||||||
β-D-Phe | ||||||||||||
1.28 | ||||||||||||
1.19 | ||||||||||||
139 | ||||||||||||
1/0.9/109 | 0.68 | 78 | 1.71 | 96 | 611 | 92 | −1.13 | |||||
17a | α-L-Chg | 1.23 | 14.3 | 177 | 1/12/144 | 2.88 | 86 | 20.5 | 101 | 250 | 52 | −1.26 |
17b | β-L-Chg | 1.66 | 1.30 | 118 | 1/0.8/71 | 5.33 | 86 | 3.57 | 96 | 282 | 59 | −1.26 |
18a | α-L-Abu | 0.76 | 37.5 | 144 | 1/49/189 | 5.12 | 88 | 98.2 | 104 | 942 | 61 | −2.34 |
18b | β-L-Abu | 1.83 | 1.30 | 201 | 1/0.7/110 | 5.47 | 83 | 2.22 | 100 | 572 | 72 | −2.34 |
19a | α-β-Ala | 1.30 | 60.0 | 182 | 1/46/140 | 3.52 | 99 | 96.4 | 97 | 186 | 78 | −3.18 |
19b | β-β-Ala | 1.04 | 13.9 | 71.4 | 1/13/69 | 5.74 | 78 | 20.1 | 99 | 622 | 67 | −3.18 |
20a | α-GABA | 0.77 | 12.5 | |||||||||
88 | 330 | 50 | −1.02 | |||||||||
21b | β-L-Val-L-Tyr | 0.44 | 1.38 | 390 | 1/3.1/886 | 0.16 | 73 | 1.56 | 89 | 1884 | 63 | −1.02 |
22a | β-Gly-Gly | 4.62 | 7.52 | 203 | 1/1.6/44 | 4.39 | 85 | 2.84 | 102 | 885 | 75 | −4.27 |
In the current context of the ‘opioid crisis’, the development of new opioid analgesics with improved pharmacology (i.e., efficacy in various pain conditions and reduced capability of inducing unwanted side effects) is of crucial clinical and public health attention. Diverse opioid analgesic discovery efforts are therefore made towards identifying effective and well-tolerated opioids that have an improved benefit/risk ratio compared with currently available drugs.
The basis for drug discovery targeting peripheral opioid receptors is supported by the knowledge that opioid receptors are expressed in the CNS, PNS and peripheral tissues. Furthermore, activating opioid receptors in the periphery leads to an effective analgesic response, and the most serious opioid-related adverse effects (i.e., apnea, sedation, physical dependence and addiction) are due to the activation of opioid receptors in the CNS. Thus, peripherally restricted opioids are viewed as viable targets to avoid many of the lethal side effects associated with opioids targeting the CNS.
In this entry, different peripheralization strategies applied to opioids are discussed. Emphasis was placed on the morphinan class of opioid ligands represented by morphine and its structurally related analogues that are used extensively not only clinically but also as experimental tools and that are important as scaffolds for the design of new ligands. Broad chemical and pharmacological work was performed on modifications of the morphinan scaffold to reduce the ability to cross the BBB, and substantial achievements have been made in the field, increasing the feasibility for clinical application. Researchers discussed chemical variations on the morphinan skeleton to increase the hydrophilicity, such as quaternization of the morphinan nitrogen (N17), the introduction of polar/ionizable substituents at C-6 position (i.e., amino acid, sulfation and glucuronidation), and nanocarrier-based approaches to selectively deliver morphine to peripheral tissue. Although the available preclinical and clinical data are favorable to the potential use of these compounds, their clinical impact, and the extent to which they will replace existing opioids, needs further investigations.