Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain
Abstract
1. Introduction
2. Peripheralization Strategies Applied to Morphinans
2.1. Quaternization of the Morphinan Nitrogen
2.2. Introduction of Hydrophilic Substituents at Position 6
2.2.1. 6-Amino-acid-substituted 14-Alkoxymorphinans
2.2.2. 6-O-Sulfate Esters of Morphine and Codeine
2.2.3. Morphine-6-glucuronide
2.3. Nanocarrier-Based Approaches of Drug Delivery
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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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. |
Compound | R | Opioid Receptor Binding a | Agonist Activity b | clogD7.4 c | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
MOR Ki (nM) | DOR Ki (nM) | KOR Ki (nM) | Ki Ratio MOR/DOR/KOR | MOR EC50 (nM) | MOR % stim. | DOR EC50 (nM) | DOR % stim. | KOR EC50 (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 | |
HS-730 (2a) | α-Gly | 0.89 | 15.4 | 43.2 | 1/7/49 | 1.16 | 99 | 9.61 | 103 | 399 | 87 | −3.35 |
HS-731 (2b) | β-Gly | 0.83 | 7.86 | 44.8 | 1/9.5/54 | 3.78 | 98 | 7.92 | 103 | 361 | 82 | −3.35 |
HS-935 (3a) | α-L-Ala | 0.77 | 26.9 | 142 | 1/35/184 | 1.34 | 97 | 9.55 | 93 | 214 | 51 | −2.81 |
HS-936 (3b) | β-L-Ala | 1.90 | 7.71 | 63.7 | 1/4.1/34 | 6.24 | 87 | 5.20 | 104 | 392 | 64 | −2.81 |
HS-937 (4a) | α-L-Phe | 0.95 | 3.67 | 28.5 | 1/3.9/30 | 0.38 | 93 | 0.39 | 102 | 219 | 39 | −1.13 |
HS-938 (4b) | β-L-Phe | 2.58 | 1.03 | 151 | 1/0.4/59 | 6.76 | 99 | 0.48 | 94 | 1172 | 81 | −1.13 |
5a | α-L-Ser | 2.21 | 5.32 | 196 | 1/2.4/89 | 1.60 | 87 | 13.9 | 101 | 1213 | 44 | −3.89 |
5b | β-L-Ser | 2.14 | 5.29 | 152 | 1/2.5/71 | 3.56 | 101 | 6.98 | 98 | 201 | 88 | −3.89 |
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 | 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 | 24.7 | 93 | 6.23 | 95 | 774 | 60 | −1.41 |
9a | α-L-Trp | 0.36 | 1.02 | 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 | 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 | 45.6 | 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 | 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 |
Compound | R | Opioid Receptor Binding, Ki (nM) a | clogD7.4 b | |||
---|---|---|---|---|---|---|
MOR | DOR | KOR | Ki Ratio MOR/DOR/KOR | |||
POMO (23) | 0.073 | 0.13 | 0.30 | 1/1.8/4.1 | 2.89 | |
24a | α-Gly | 0.19 | 0.22 | 0.73 | 1/1.2/3.8 | −0.85 |
24b | β-Gly | 0.16 | 0.19 | 0.81 | 1/1.2/5.1 | −0.85 |
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 | ||||
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 |
5a | α-L-Ser | 32.1 | |||
6b | β-L-Val | 117 | |||
7a | α-L-Lys | 20.6 | |||
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 | 14.0 | |||
16a | α-D-Phe | 18.1 | |||
16b | β-D-Phe | 250 | |||
17a | α-L-Chg | 20.6 | |||
18a | α-L-Abu | 17.5 | |||
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] |
Visceral pain | |||
Acetic-acid-induced writhing assay (mouse) | i.c.v. s.c. | 0.49 pmol/mouse 51 nmol/kg | [42] [42] |
s.c. | 27.5 µg/kg | [36] | |
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] [41] |
Neuropathic pain, sciatic nerve ligation—Mechanical hyperalgesia (rat) | i.pl. | 441 nmol | [44] |
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 | |
Fentanyl | 38.6 | 1.66 | 23 | |
14-OMO (1) | 14.9 | 0.172 | 87 | |
HS-730 (2a) | α-Gly | 58.5 | 0.031 | 1887 |
HS-731 (2b) | β-Gly | 29.0 | 0.030 | 967 |
HS-935 (3a) | α-L-Ala | 68.9 | 0.121 | 569 |
HS-936 (3b) | β-L-Ala | 53.4 | 0.082 | 651 |
HS-937 (4a) | α-L-Phe | 315 | 0.063 | 5000 |
HS-938 (4b) | β-L-Phe | >3600 | 0.776 | >4600 |
Compound | Opioid Receptor Binding, Ki (nM) a | |||
---|---|---|---|---|
MOR | DOR | KOR | Ki Ratio MOR/DOR/KOR | |
Morphine | 4.37 | 2951 | 113 | 1/675/26 |
Codeine | 737 | - b | - | - |
M6SU | 11.5 | 525 | 275 | 1/46/24 |
C6SU | 96.9 | 968 b | - | 1/10/- |
14-O-MeM6SU | 1.12 | 10.2 | 295 | 1/9/263 |
14-O-MeC6SU | 3.37 | 346 | 246 | 1/103/73 |
Compound | MVD Bioassay | [35S]GTPγS Binding Assay | ||
---|---|---|---|---|
EC50 (nM) | Tissue | EC50 (nM) | Emax (%) | |
Morphine | 347 | Rat brain Guinea-pig brain | 250 462 | 129 119 |
Codeine | >1000 | Rat brain Guinea-pig brain | - a - | 110 104 |
M6SU | 103 | Rat brain Guinea-pig brain | 105 - | 133 - |
C6SU | >1000 | Rat brain Guinea-pig brain | >10,000 - | 121 102 |
14-O-MeM6SU | 4.38 | Rat brain Guinea-pig brain | 19.1 - | 201 - |
14-O-MeC6SU | 238 | Rat brain Guinea-pig brain | 301 >1000 | 128 130 |
Compound | Pain Model (Species) | ED50 (Systemic Administration) | ED50 (Central Administration) | Reference |
---|---|---|---|---|
Morphine | hot-plate test (mouse) | 4.5 mg/kg, s.c. | [50] | |
hot water tail-flick test (rat) | 3.41 mg/kg, i.p. | [64] | ||
radiant heat tail-flick test (mouse) | 5.5 nmol/mouse, i.c.v. | [59] | ||
radiant heat tail-flick test (mouse) | 314 ng/mouse, i.c.v. | [52] | ||
radiant heat tail-flick test (rat) | 6221 nmol/kg, s.c. | 38.6 nmol/rat, i.c.v | [58] | |
radiant heat tail-flick test (rat) | 2.68 mg/kg, i.p. | 3.51 µg/rat, i.t. | [60] | |
radiant heat tail-flick test (rat) | 9.1 mg/kg, p.o. | [60] | ||
acetic-acid-induced writhing assay (mouse) | 238.6 nmol/kg, i.p. | 2.02 nmol/mouse, i.c.v. | [61] | |
formalin-induced inflammatory pain (rat) | Phase II: 0.259 mg/kg, i.p. | [61] | ||
formalin-induced inflammatory pain (rat) | Phase I and II: 3884, 7769, 15,538, 31,075 nmol/kg, s.c. a | [65] | ||
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] | |
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] |
Compound | Pain Model (Species) | ED50 Ratio Peripheral/Central Administration | Reference |
---|---|---|---|
Fentanyl | radiant heat tail-flick test (rat) | 23 | [50] |
Morphine | radiant heat tail-flick test (rat) | 172 | [40] |
159 | [58] | ||
125 | [53] | ||
acetic-acid-induced writhing assay (rat) | 118 | [61] | |
M6SU | radiant heat tail-flick test (rat) | 25,493 | [58] |
acetic-acid-induced writhing assay (mouse) | 221,444 | [62] | |
14-O-MeM6SU | radiant heat tail-flick test (rat) | 11,615 | [58] |
acetic-acid-induced writhing assay (mouse) | 51,177 | [62] | |
14-O-MeC6SU | radiant heat tail-flick test (rat) | 314 | [53] |
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Schmidhammer, H.; Al-Khrasani, M.; Fürst, S.; Spetea, M. Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain. Molecules 2023, 28, 4761. https://doi.org/10.3390/molecules28124761
Schmidhammer H, Al-Khrasani M, Fürst S, Spetea M. Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain. Molecules. 2023; 28(12):4761. https://doi.org/10.3390/molecules28124761
Chicago/Turabian StyleSchmidhammer, Helmut, Mahmoud Al-Khrasani, Susanna Fürst, and Mariana Spetea. 2023. "Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain" Molecules 28, no. 12: 4761. https://doi.org/10.3390/molecules28124761
APA StyleSchmidhammer, H., Al-Khrasani, M., Fürst, S., & Spetea, M. (2023). Peripheralization Strategies Applied to Morphinans and Implications for Improved Treatment of Pain. Molecules, 28(12), 4761. https://doi.org/10.3390/molecules28124761