The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative
Abstract
:1. Introduction
2. Results
2.1. Monoamine Uptake Transporter Inhibition
2.2. Serotonergic Receptor Interactions: Binding Affinity and Activation Potency
2.3. Monoamine Transporter and Non-Serotonergic Receptor Binding Interactions
2.4. Transporter-Mediated Monoamine Efflux
3. Discussion
3.1. Monoamine Transporter Inhibition and Transporter-Mediated Efflux
3.2. Serotonergic Receptor Binding and Activation Interactions
3.3. Monoamine Transporter and Non-Serotonergic Receptor Binding Interactions
4. Materials and Methods
4.1. Compounds
4.2. Monoamine Uptake Transporter Inhibition
4.3. Monoamine Efflux Mediated by the Transporters
4.4. Radioligand Binding, Activation Potency, and Efficacy at the 5-HT Receptors
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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NET | DAT | SERT | DAT/SERT Ratio | |
---|---|---|---|---|
IC50 [μM] (95% CI) | IC50 [μM] (95% CI) | IC50 [μM] (95% CI) | Ratio (95% CI) | |
Pyrovalerone cathinones | ||||
α-PPP | 0.64 (0.41–0.99) | 0.56 (0.40–0.76) | >1000 | >1000 |
α-PVP | 0.02 (0.01–0.05) | 0.03 (0.02–0.04) | 279 (209–372) | >1000 |
α-PHP | 0.06 (0.03–0.12) | 0.06 (0.05–0.08) | 245 (173–348) | >1000 |
4-MePPP | 0.64 (0.43–0.95) | 0.75 (0.58–0.97) | 55 (38–78) | 72 (39–134) |
Pyrovalerone | 0.06 (0.04–0.09) | 0.05 (0.04–0.08) | 13 (10–18) | 256 (125–450) |
MPHP | 0.07 (0.05–0.10) | 0.06 (0.05–0.08) | 11 (8.0–15) | 169 (100–300) |
MDPPP | 1.7 (1.3–2.2) | 0.54 (0.37–0.79) | 43 (34–55) | 80 (43–149) |
MDPBP | 0.14 (0.10–0.19) | 0.07 (0.06–0.09) | 11 (8.6–15) | 155 (96–250) |
MDPV | 0.05 (0.04–0.08) | 0.03 (0.03–0.05) | 8.4 (6.6–11) | 241 (132–367) |
MDPHP | 0.06 (0.03–0.13) | 0.05 (0.04–0.07) | 9 (6.0–14) | 184 (86–350) |
MOPPP | 8.7 (6.3–12) | 4.6 (3.4–6.3) | 94 (65–135) | 20 (4.0–40) |
4F-PBP | 0.61 (0.43–0.87) | 0.50 (0.36–0.69) | 177 (97–325) | 356 (141–903) |
Other | ||||
NEH | 0.17 (0.12–0.24) | 0.18 (0.14–0.24) | 47 (38–60) | 264 (158–429) |
Reference substances | ||||
MDMA | 0.41 (0.33–0.52) | 13 (11–16) | 1.6 (1.2–2.2) | 0.12 (0.08–0.20) |
Amphetamine | 0.07 (0.05–0.1) a | 1.3 (0.8–2.0) a | 45 (24–85) a | 35 (12–106) a |
h5-HT1A | h5-HT2A | h5-HT2B | h5-HT2C | ||
---|---|---|---|---|---|
Receptor Binding | Receptor Binding | Activation Potency | Activation Potency | Receptor Binding | |
Ki ± SD [μM] | Ki ± SD [μM] | EC50 ± SD [μM] | EC50 ± SD [μM] | Ki ± SD [μM] | |
[3H]-8-OH-DPAT | [3H]-Ketanserin | [3H]-Mesulgerine | |||
Pyrovalerone cathinones | |||||
α-PPP | 0.7 ± 0.3 | 1.1 ± 0.3 | >20 | >20 | >15 |
α-PVP | 6.1 ± 0.7 | >13 | >20 | >20 | >15 |
α-PHP | 11 ± 5.3 | >13 | >20 | >20 | >15 |
4-MePPP | 12 ± 2.2 | 1.3 ± 0.4 | >10 | >10 | >5.1 |
Pyrovalerone | 13 ± 1.4 | >13 | >20 | >20 | >15 |
MPHP | 13 ± 1.9 | 7.3 ± 1.2 | >20 | >20 | >15 |
MDPPP | 1.9 ± 0.8 | 8.0 ± 1.2 | >20 | >20 | >15 |
MDPBP | 9.0 ± 1.5 | >13 | >20 | >20 | >15 |
MDPV | 7.7 ± 0.6 | >13 | >20 | >20 | >15 |
MDPHP | 13 ± 1.9 | >13 | >20 | >20 | >15 |
MOPPP | >17 | >13 | >20 | >20 | >15 |
4F-PBP | 6.0 ± 3.4 | >13 | >20 | >20 | >15 |
Other | |||||
NEH | >17 | >13 | >20 | >20 | >15 |
Reference substances | |||||
MDMA | 11 ± 2.0 a | 6.3 ± 2.4 b | 6.1 ± 0.3 b | >20 b | 4.4 ± 0.8 a |
Amphetamine | 6.7 ± 1.4 c | >13 c | NA | 9.4 ± 1.6 b | >13 c |
hNET | hDAT | hSERT | D2 | α1A | α2A | Human TAAR1 | Rat TAAR1 | Mouse TAAR1 | |
---|---|---|---|---|---|---|---|---|---|
Receptor Binding | Activation Potency | Receptor Binding | |||||||
Ki ± SD [μM] | EC50 ± SD [μM] | Ki ± SD [μM] | |||||||
N-Methyl-[3H]-nisoxetine | [3H]-WIN-35,428 | [3H]-Citalopram | [3H]-Spiperone | [3H]-Prazosin | [3H]-Rauwolscine | [3H]-RO5166017 | |||
Pyrovalerone cathinones | |||||||||
α-PPP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
α-PVP | 0.06 ± 0.02 d | 0.007 ± 0.002 d | >30 d | >10 d | >15 d | >20 d | NA | 16 ± 6.4 d | >20 d |
α-PHP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
4-MePPP | 2.5 ± 0.7 | 0.3 ± 0.02 | >7.4 | >13 | 2.2 ± 0.1 | >4.7 | NA | NA | NA |
Pyrovalerone | 0.06 ± 0.01 c | 0.03 ± 0.01 c | 5.0 ± 0.3 c | >30 c | >6 c | >20 c | NA | >12.5 c | >10 c |
MPHP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
MDPPP | 3.5 ± 1.0 d | 0.18 ± 0.05 d | 12 ± 1.0 d | >10 d | >15 d | 14 ± 0.9 d | NA | 16 ± 6.7 d | >20 d |
MDPBP | 1.1 ± 0.1 d | 0.02 ± 0.002 d | 4.1 ± 1.2 d | >20 d | >4.9 d | 9.4 ± 1.6 d | NA | >20 d | >20 d |
MDPV | 0.08 ± 0.02 c | 0.01 ± 0.002 c | 2.9 ± 0.1 c | >30 c | >6 c | >20 c | >30 b | 7.2 ± 1.1 c | >10 c |
MDPHP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
MOPPP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
4F-PBP | NA | NA | NA | NA | NA | NA | NA | NA | NA |
Other | |||||||||
NEH | NA | NA | NA | NA | NA | NA | NA | NA | NA |
Reference substances | |||||||||
MDMA | >8.7 a | >8.5 a | >7.5 a | >13 a | 6.9 ± 1.2 a | 4.6 ± 1.1 a | 35 ± 21 b | 0.25 ± 0.01 a | 3.1 ± 0.7 a |
Amphetamine | 1.0 ± 0.6 c | 5.7 ± 3.8 c | >25 c | >30 c | >6.0 c | 2.8 ± 0.8 c | 2.8 ± 0.8 b | 0.23 ± 0.18 c | 0.09 ± 0.06 c |
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Kolaczynska, K.E.; Thomann, J.; Hoener, M.C.; Liechti, M.E. The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative. Int. J. Mol. Sci. 2021, 22, 8277. https://doi.org/10.3390/ijms22158277
Kolaczynska KE, Thomann J, Hoener MC, Liechti ME. The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative. International Journal of Molecular Sciences. 2021; 22(15):8277. https://doi.org/10.3390/ijms22158277
Chicago/Turabian StyleKolaczynska, Karolina E., Jan Thomann, Marius C. Hoener, and Matthias E. Liechti. 2021. "The Pharmacological Profile of Second Generation Pyrovalerone Cathinones and Related Cathinone Derivative" International Journal of Molecular Sciences 22, no. 15: 8277. https://doi.org/10.3390/ijms22158277