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RO5203648
Clinical data
Other namesRO-5203648
Drug classTrace amine-associated receptor 1 (TAAR1) partial agonist
Identifiers
  • (4S)-4-(3,4-dichlorophenyl)-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC9H8Cl2N2O
Molar mass231.08 g·mol−1
3D model (JSmol)
  • C1[C@@H](N=C(O1)N)C2=CC(=C(C=C2)Cl)Cl
  • InChI=1S/C9H8Cl2N2O/c10-6-2-1-5(3-7(6)11)8-4-14-9(12)13-8/h1-3,8H,4H2,(H2,12,13)/t8-/m1/s1
  • Key:HGGPGNSCBBAGJN-MRVPVSSYSA-N

RO5203648 is a trace amine-associated receptor 1 (TAAR1) partial agonist.[1][2][3] It is a potent and highly selective partial agonist of both rodent and primate TAAR1.[2][3] The drug suppresses the effects of psychostimulants like cocaine and methamphetamine.[1][2] It also produces a variety of other behavioral effects, such as antidepressant-like, antipsychotic-like, and antiaddictive effects.[1][2][4] Research with RO5203648 has led to interest in TAAR1 agonists for potential treatment of drug addiction.[1] RO5203648 itself was not developed for potential medical use due to poor expected human pharmacokinetics.[3]

Pharmacology

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Pharmacodynamics

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Actions

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RO5203648 binds to the mouse, rat, cynomolgus monkey, and human TAAR1 all with high affinity (Ki = 0.5–6.8 nM).[1][2] It is a potent partial agonist in all species (EC50Tooltip half-maximal effective concentration = 4.0 to 31 nM), with an efficacy of 48 to 73% relative to the endogenous TAAR1 agonists β-phenethylamine and tyramine and the TAAR1 full agonist RO5166017.[1][2][3] RO5203648 is highly selective for the TAAR1, showing ≥130-fold selectivity for the mouse TAAR1 over 149 other targets.[2][3]

RO5203648 at TAAR1 in different species[2][3][1]
Species Affinity (Ki, nM) EC50Tooltip half-maximal effective concentration (nM) EmaxTooltip maximal efficacy (%)
Mouse 0.5 2.1–4.0 48–71%
Rat 1.0 6.8 59%
Monkey 2.6 31 69%
Human 6.8 30 73%

Effects

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RO5203648 has been found to increase the firing rate of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo.[1][5][2] This is in contrast to the TAAR1 full agonist RO5166017, which suppresses their firing rates, but is analogous to the TAAR1 antagonist EPPTB, which dramatically increases their firing rates.[1][5][2] RO5203648 failed to show these effects in the neurons of TAAR1 knockout mice, indicating that its actions are mediated by interactions with the TAAR1.[2] RO5203648 alone does not affect electrically evoked dopamine release or reuptake (as measured by tau) in rat nucleus accumbens (NAc) slices ex vivo.[5][6] Conversely, RO5203648 prevented cocaine-induced dopamine elevations in this system without affecting the dopamine reuptake inhibition of cocaine.[1][5][6] As such, its inhibition of cocaine's dopaminergic actions is likely to be independent of dopamine transporter (DAT) interactions.[1][6] RO5203648 did not affect methamphetamine-induced dopamine efflux or reuptake inhibition in rat striatal synaptosomes in vitro.[7][8][4] However, RO5203648 blunted and delayed methamphetamine-induced dopamine elevations in the NAc in rodents in vivo.[5][4] Hence, as with cocaine, RO5203648's regulation of methamphetamine's actions appears to be independent of DAT interactions.[7][5][4]

Some in-vitro studies have suggested that TAAR1 agonism by amphetamines and β-phenethylamine may mediate induction of monoamine release and reuptake inhibition by these agents.[9][10][11][12][13][14][14] However, a subsequent study failed to replicate these findings under similar conditions.[7] In addition, as previously described, RO5203648 did not affect methamphetamine-induced dopamine release and reuptake inhibition in synaptosomes in vitro.[7][8][5][4] The dopamine elevations and psychostimulant-like effects of amphetamines are not only preserved but are actually augmented in TAAR1 knockout mice in vivo.[9][8][15][16] Concordant in-vivo findings have been made with amphetamines combined with TAAR1 agonists and antagonists as well as with TAAR1 overexpression.[8] It appears that TAAR1 agonism by amphetamines, such as amphetamine, methamphetamine, and MDMA, auto-inhibits their monoaminergic effects.[17][18][19] Conversely, most cathinones lack TAAR1 agonism, and this might enhance their effects compared to amphetamines.[18][20]

RO5203648 does not significantly affect basal locomotion.[2] Conversely, the drug has been found to dose-dependently suppress cocaine-induced hyperlocomotion in mice and rats, whereas it only suppressed dextroamphetamine-induced hyperactivity in rats but not in mice.[1][21][5][2] RO5203648 reduced early but potentiated late hyperlocomotion induced by methamphetamine.[1][4] With chronic administration of RO5203648 and methamphetamine, RO5203648 dose-dependently and progressively decreased methamphetamine-induced hyperlocomotion.[1][4] TAAR1 full agonists like RO5166017 and RO5256390 also suppress psychostimulant-induced hyperlocomotion.[21] RO5203648 suppressed spontaneous hyperactivity in a novel environment in dopamine transporter (DAT) knockout mice, similarly to antipsychotics like haloperidol and olanzapine.[2][22] RO5203648 has also been found to suppress hyperlocomotion induced by the NMDA receptor antagonist L-687,414 or in genetically modified mice with a hypoactive NMDA receptor.[1][2] The effects of RO5203648 on hyperdopaminergic- and hypoglutamatergic-mediated hyperlocomotion are similar to those of the TAAR1 full agonist RO5166017.[21][2]

The drug has shown anti-cataleptic, pro-cognitive, antipsychotic-like, antidepressant-like, anxiolytic-like, anti-addictive, and wakefulness-promoting effects in animals.[2][3][1][6][23] RO5203648, as well as the TAAR1 full agonist RO5256390, have been found to suppress cocaine and methamphetamine self-administration, and hence presumably their rewarding and reinforcing effects.[1][5][23] RO5203648 also blocked methamphetamine-induced locomotor sensitization, but cross-sensitized with methamphetamine at the highest dose.[5][4] RO5203648 by itself is not self-administered in animals, suggesting that it lacks reinforcing effects and misuse liability of its own.[21][4]

Pharmacokinetics

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RO5203648 showed favorable pharmacokinetics orally and intravenously in mice, rats, and monkeys.[2] However, it was found to be very rapidly metabolized in human hepatocytes in vitro.[3]

Chemistry

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In terms of chemical structure, RO5203648 is a 2-aminooxazoline derivative.[3][24] This group also includes a number of other selective TAAR1 ligands, including the near-full agonist RO5166017, the full agonist RO5256390, and the partial agonist RO5263397.[3] RO5203648 is also very closely structurally related to the monoamine releasing agents and psychostimulants aminorex and clominorex.[24]

History

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RO5203648 was first described by 2012.[2] It was the first selective TAAR1 partial agonist to be developed.[1][2][3] The drug followed the first TAAR1 antagonist EPPTB and the first TAAR1 full agonist RO5166017.[2] It was under investigation for potential clinical use in humans, but showed indication of very rapid human metabolism in vitro.[3] As a result, it was deselected from development, and other compounds, such as the TAAR1 partial agonist RO5263397, were pursued instead.[3]

See also

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  • RO5073012 – TAAR1 weak partial agonist
  • RO5166017 – TAAR1 partial or full agonist
  • RO5256390 – TAAR1 partial or full agonist
  • RO5263397 – TAAR1 partial agonist
  • EPPTB – TAAR1 antagonist/inverse agonist

References

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  1. ^ a b c d e f g h i j k l m n o p q r Wu R, Li JX (December 2021). "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs. 35 (12): 1239–1248. doi:10.1007/s40263-021-00871-4. PMC 8787759. PMID 34766253.
  2. ^ a b c d e f g h i j k l m n o p q r s t u Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velázquez-Sánchez C, Sotnikova TD, et al. (December 2012). "Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics". Biol Psychiatry. 72 (11): 934–942. doi:10.1016/j.biopsych.2012.05.014. PMID 22705041.
  3. ^ a b c d e f g h i j k l m Galley G, Beurier A, Décoret G, Goergler A, Hutter R, Mohr S, et al. (February 2016). "Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists". ACS Med Chem Lett. 7 (2): 192–197. doi:10.1021/acsmedchemlett.5b00449. PMC 4753552. PMID 26985297.
  4. ^ a b c d e f g h i Cotter R, Pei Y, Mus L, Harmeier A, Gainetdinov RR, Hoener MC, et al. (2015). "The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects". Front Neurosci. 9: 39. doi:10.3389/fnins.2015.00039. PMC 4327507. PMID 25762894. In the synaptosomal preparation RO5203648 did not affect METH-induced striatal DA release and DA uptake inhibition, suggesting that RO5203648 regulation of METH's behavioral effects is unlikely to depend on direct, local actions at the DAT. As previously indicated, the in vivo microdialysis data revealed transient but significant reduction in METH-induced DA overflow following RO5203648 treatment.
  5. ^ a b c d e f g h i j Pei Y, Asif-Malik A, Canales JJ (2016). "Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications". Front Neurosci. 10: 148. doi:10.3389/fnins.2016.00148. PMC 4820462. PMID 27092049. [...] while the selective TAAR1 full agonists, RO5166017 and RO5256390, decreased the firing frequency of DA neurons in the VTA and of 5-HT neurons in the dorsal raphe nucleus, the partial agonists, RO5203648 and RO5263397, enhanced the firing rate of these same neurons, [...] the partial agonist, RO5203648, prevented cocaine-induced DA-overflow, in vitro, (Pei et al., 2014) and transiently attenuated methamphetamine-induced DA accumulation in the NAc, in vivo (Cotter et al., 2015), although it increased the firing rate of DA neurons in the VTA under basal conditions. [...] Revel and collaborators provided the first evidence that the partial agonist, RO5203648, decreased cocaine-induced locomotor activity and self-administration in rats (Revel et al., 2012b). Subsequent work revealed that the partial and full agonists, RO5203648 and RO5256390, respectively, both produced downward shifts in the dose-response curve for cocaine self-administration and prevented cocaine-induced lowering of ICSS thresholds (Pei et al., 2015), indicating that partial or full TAAR1 activation blocks the reinforcing properties of cocaine. [...] In the case of methamphetamine, the partial agonists, RO5203648, and RO5263397, reduced methamphetamine-induced behavioral sensitization, and self-administration (Jing et al., 2014; Cotter et al., 2015). [...] using a progressive ratio schedule of reinforcement, the partial agonist, RO5203648, decreased the break point for cocaine self-administration but enhanced responding for food (Pei et al., 2014), [...] Although, the mechanisms by which TAAR1 activation decreases motor stimulant effects are not well-understood, using fast-scan cyclic voltammetry we have shown previously that activation of TAAR1 with the partial agonist, RO5203648, prevented the potentiation of DA transmission caused by cocaine in the NAc without affecting DA uptake kinetics. This suggests that the TAAR1 agonist attenuated cocaine-stimulated DA overflow by mechanisms other than direct interference with DA uptake (Pei et al., 2014).
  6. ^ a b c d Pei Y, Lee J, Leo D, Gainetdinov RR, Hoener MC, Canales JJ (September 2014). "Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking". Neuropsychopharmacology. 39 (10): 2299–2308. doi:10.1038/npp.2014.88. PMC 4138750. PMID 24722355. [The] TAAR1 partial agonist [RO5203648 (1 μM)] by itself did not affect significantly [evoked] DA outflow (107±21%, p>0.05, vs predrug values) or tau measure (106±14% vs predrug levels, p>0.05), suggesting that DA release and uptake are not influenced by the TAAR1 partial agonist. However, co-application of RO5203648 with cocaine significantly reduced cocaine-induced DA efflux (95±9%, p<0.05 vs cocaine-induced levels), without altering the effects of cocaine on tau measure of DA uptake (Tau; 150±13%, p<0.05 vs predrug levels, p<0.05 vs cocaine-induced levels) (Figures 3b and c). [...] neurochemical measurements of DA overflow in the nucleus accumbens showed the ability of RO5203648 to reduce cocaine-induced DA accumulation without significantly altering DA uptake rates, [...] We used fast cycling voltammetry in slices through the nucleus accumbens to assess the ability of RO5203648 to modulate cocaine-stimulated DA transmission. As predicted, RO5203648 diminished cocaine-induced DA overflow in the nucleus accumbens. However, RO5203648 did not significantly affect the tau measure of DA uptake in the presence of cocaine, thus suggesting that TAAR1 regulation of cocaine's effects on DA levels is likely to be independent of direct actions on the DAT. [...] As the DA uptake blocking activity of cocaine seems not to be affected by RO5203648 pretreatment, it is likely that TAAR1 activation causes a decrease in DA release kinetics resulting in less accumulation of extracellular DA resulting from blockade of the DAT by cocaine.
  7. ^ a b c d Miner NB, Phillips TJ, Janowsky A (October 2019). "The Role of Biogenic Amine Transporters in Trace Amine-Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity". J Pharmacol Exp Ther. 371 (1): 36–44. doi:10.1124/jpet.119.258970. PMC 6750185. PMID 31320495. We were unable to replicate the results of Xie and Miller (2009) under similar in vitro conditions (Fig. 3). There was no difference in IC50 values for [3H]DA uptake inhibition by MA between synaptosomes from Taar1 WT and KO mice. [...] our results do not support an earlier hypothesis that TAAR1 modulates DAT (Xie and Miller, 2007, 2009; Xie et al., 2008b), as there was no evidence of an interaction under conditions described above. Recent reports support our findings that the DAT is unaffected by TAAR1. Coadministration of MA and the TAAR1 partial agonist RO523648 did not alter [3H]DA uptake and release in striatal synaptosomes in rats (Cotter et al., 2015). [...] Given the lack of interaction, DAT is an improbable mediator of TAAR1 regulation of MA-induced neurotoxicity. [...] activation of TAAR1 did not modulate in vitro MA-impairment of DAT function or DAT expression. As TAAR1 activation did not alter the function or expression of DAT in whole synaptosomes [...], these results indicate TAAR1 does not interact with these transporters on the plasma membrane [...]
  8. ^ a b c d Liu J, Wu R, Li JX (March 2020). "TAAR1 and Psychostimulant Addiction". Cell Mol Neurobiol. 40 (2): 229–238. doi:10.1007/s10571-020-00792-8. PMC 7845786. PMID 31974906.
  9. ^ a b Miller GM (January 2011). "The emerging role of trace amine-associated receptor 1 in the functional regulation of monoamine transporters and dopaminergic activity". J Neurochem. 116 (2): 164–176. doi:10.1111/j.1471-4159.2010.07109.x. PMC 3005101. PMID 21073468.
  10. ^ Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC 4724540. PMID 26644139.
  11. ^ Xie Z, Miller GM (April 2007). "Trace amine-associated receptor 1 is a modulator of the dopamine transporter". J Pharmacol Exp Ther. 321 (1): 128–136. doi:10.1124/jpet.106.117382. PMID 17234899.
  12. ^ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J Pharmacol Exp Ther. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC 2700171. PMID 19364908.
  13. ^ Xie Z, Miller GM (May 2008). "Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain". J Pharmacol Exp Ther. 325 (2): 617–628. doi:10.1124/jpet.107.134247. PMID 18182557.
  14. ^ a b Miller GM, Xie Z (2010). "Trace amine associated receptor 1 mediates methamphetamine effects on monoamine transporter function". The FASEB Journal. 24 (S1). doi:10.1096/fasebj.24.1_supplement.578.5. ISSN 0892-6638.
  15. ^ Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID 18083911.
  16. ^ Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacol Biochem Behav. 101 (2): 201–207. doi:10.1016/j.pbb.2011.10.025. PMC 3288391. PMID 22079347.
  17. ^ Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Topics in Medicinal Chemistry. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN 978-3-319-48925-4. Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.
  18. ^ a b Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID 36866677. Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016).
  19. ^ Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, et al. (November 2011). "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci. 31 (47): 16928–16940. doi:10.1523/JNEUROSCI.2502-11.2011. PMC 6623861. PMID 22114263.
  20. ^ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID 26791601.
  21. ^ a b c d Liu JF, Li JX (2018). "TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg". Front Pharmacol. 9: 279. doi:10.3389/fphar.2018.00279. PMC 5881156. PMID 29636691. RO5203648 alone did not maintain self-administration behavior using a substitution procedure in rats self-administering METH, indicating that RO5203648 itself had no reinforcing effect (Cotter et al., 2015). [...] TAAR1 partial agonist RO5203648 dose-dependently reduced cocaine-induced hyperlocomotion and cocaine self-administration (Revel et al., 2012a). [...] Pei et al. also showed that the partial TAAR1 agonist RO5203648 and the full agonist RO5256390 decreased cocaine self-administration and cocaine-seeking behaviors (Pei et al., 2014, 2015). [...] Cotter et al. showed that the selective TAAR1 partial agonist RO5203648 inhibited METH-induced increase in extracellular dopamine level in the NAc in vivo (Cotter et al., 2015). However, RO5203648 did not affect METH-mediated inhibition of DA efflux and reuptake in striatal synaptosomes in vitro. Given that the in vivo data and in vitro results are not expected to be always consistent, these results might to some extent suggest that TAAR1 in the NAc but not dorsal striatum participated in METH-induced neurochemical alterations and behaviors. In another study, it was demonstrated that RO5203648 blocked cocaine-induced DA overflow in the NAc (Pei et al., 2014). Interestingly, RO5203648 did not change the clearance of DA, indicating that TAAR1 regulating cocaine-induced DA overflow by mechanisms other than interaction with DAT (Pei et al., 2014).
  22. ^ Leo D, Sukhanov I, Zoratto F, Illiano P, Caffino L, Sanna F, et al. (February 2018). "Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats". J Neurosci. 38 (8): 1959–1972. doi:10.1523/JNEUROSCI.1931-17.2018. PMC 5824739. PMID 29348190.
  23. ^ a b Pei Y, Mortas P, Hoener MC, Canales JJ (December 2015). "Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds". Prog Neuropsychopharmacol Biol Psychiatry. 63: 70–75. doi:10.1016/j.pnpbp.2015.05.014. PMID 26048337.
  24. ^ a b "(S)-4-(3,4-Dichlorophenyl)-4,5-dihydrooxazol-2-amine". PubChem. Retrieved 18 December 2024.


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