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RO5263397
Clinical data
Other namesRO-5263397; Ro 5263397; Ro-5263397
Drug classTrace amine-associated receptor 1 (TAAR1) partial or full agonist
Identifiers
  • (4S)-4-(3-fluoro-2-methylphenyl)-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC10H11FN2O
Molar mass194.209 g·mol−1
3D model (JSmol)
  • CC1=C(C=CC=C1F)[C@H]2COC(=N2)N
  • InChI=1S/C10H11FN2O/c1-6-7(3-2-4-8(6)11)9-5-14-10(12)13-9/h2-4,9H,5H2,1H3,(H2,12,13)/t9-/m1/s1
  • Key:IOHOUWIYOVWGHV-SECBINFHSA-N

RO5263397, or RO-5263397, is a trace amine-associated receptor 1 (TAAR1) partial or full agonist which is used in scientific research.[1][2][3][4][5] It is the most well-studied of all of the synthetic TAAR1 ligands.[1] In addition to its use in research, RO5263397 is or was under development for potential clinical use as a medication.[6][7][8]

Pharmacology

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Pharmacodynamics

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Actions

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RO5263397 is a trace amine-associated receptor 1 (TAAR1) partial agonist to full agonist.[9][4] Its EC50Tooltip half-maximal effective concentration values are 0.12 to 7.5 nM for the mouse TAAR1 (mTAAR1), 35 to 47 nM for the rat TAAR1 (rTAAR1), 251 nM at the cynomolgus monkey TAAR1, and 17 to 85 nM for the human TAAR1 (hTAAR1).[3][9][4][5] Its intrinsic activity (Emax) is 59 to 100% at the mTAAR1, 69 to 76% at the rTAAR1, 85% at the cynomolgus monkey TAAR1, and 81 to 82% at the hTAAR1.[9][4][5]

RO5263397 at TAAR1 in different species[9][4][5][3]
Species Affinity (Ki, nM) EC50Tooltip half-maximal effective concentration (nM) EmaxTooltip maximal efficacy (%)
Mouse 0.9 0.12–7.5 59–100%
Rat 9.1 35–47 69–76%
Monkey 24 251 85%
Human 4.1 17–85 81–82%

The drug was found to have 392-fold higher potency at the mTAAR1 compared to the hTAAR1 in vitro in one comparative study, although it still activated the hTAAR1 with low-nanomolar potency (EC50 = 0.12 ).[10][5]

Effects

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RO5263397 has been found to increase the firing rates of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo.[1][4][11] This is in contrast to the high-efficacy TAAR1 agonists p-tyramine, RO5166017, and RO5256390, which inhibit these neurons in such systems, but is similar to the increased firing rates with the TAAR1 antagonist EPPTB, supporting a partially agonistic profile of RO5263397 at the mTAAR1.[1][4][11] RO5263397 can partially and dose-dependently reverse the suppressive effects of RO5256390 on monoaminergic neuron firing in brain slices ex vivo.[11] In contrast to VTA dopaminergic and DRN serotonergic neurons, RO5263397 had no effect on locus coeruleus (LC) noradrenergic neurons in the system, where the TAAR1 is notably not expressed.[11][12] The effects of RO5263397 on the firing frequencies of monoaminergic neurons are absent in TAAR1 knockout mice.[4] RO5263397 has been found to fully prevent methamphetamine-induced dopamine release in rat nucleus accumbens core (NAcc) brain slices ex vivo.[10][1][13] Conversely, RO5263397 by itself had no effect on dopamine overflow in rat NAcc slices ex vivo.[13]

RO5263397 alone has no effect on locomotor activity in rodents in vivo.[14][15][16] Similarly, RO5263397 did not affect locomotor activity in monkeys.[17] Conversely, RO5263397 has been found to dose-dependently and fully inhibit cocaine-induced hyperlocomotion in mice in vivo.[4] Likewise, it dose-dependently inhibited hyperlocomotion induced by the NMDA receptor antagonists phencyclidine (PCP) and L-687,414 in mice in vivo.[4] The TAAR1 full agonist RO5166017 and the high-efficacy TAAR1 partial agonist RO5256390, as well as the antipsychotic olanzapine, produced similar effects in these paradigms.[4] Relatedly, RO5263397 produced a pattern of brain activity in rodents similar to that of antipsychotics.[4] In addition, RO5263397 potently suppresses hyperlocomotion in dopamine transporter (DAT) knockout mice.[5] The preceding findings suggest that TAAR1 agonists like RO5263397 have antipsychotic-like properties.[1][4] In contrast to classical antipsychotics however, RO5263397 did not show extrapyramidal-like symptoms like catalepsy in mice, and instead partially prevented haloperidol-induced catalepsy, suggesting the potential for an improved tolerability profile.[4]

RO5263397 has been shown to reduce behavioral sensitization induced by cocaine in mice.[1][18][14] Similarly, it reduces the expression but not development of conditioned place preference (CPP) by cocaine in mice.[14] Analogously to cocaine, RO5263397 dose-dependently attenuates behavioral sensitization to methamphetamine, reduces self-administration of methamphetamine, and blocks reinstatement of methamphetamine-seeking behaviors in rodents.[1][15][13] It also attenuates methamphetamine-induced impulsivity in rodents.[1][19] In general, the drug has been found to suppress methamphetamine-, cocaine, and nicotine-induced stimulant-like and reinforcing effects in animals in vivo.[10] Analogous findings have been made for morphine and ethanol.[1][20][21] RO5263397 has similar effects compared to TAAR1 full agonists like RO5256390 in vivo in terms of psychostimulant modulation.[10][1] Unlike methamphetamine and other misused drugs, RO5263397 itself is not self-administered at any dose and shows no misuse liability.[1][13]

The drug has shown wakefulness-promoting, pro-cognitive-like and antidepressant-like effects in rodents and/or monkeys.[10][1][4][22][16][5][17] The wakefulness-promoting effects of RO5263397 appear to be mediated through dopaminergic signaling, specifically increased activation of dopamine D1 and D2 receptors.[23] Similarly to other TAAR1 agonists like RO5166017 and RO5256390, RO5263397 shows aversive effects in animals.[24][25] The drug has been reported to affect measures of executive function in rats, such as increasing attention, decreasing cognitive flexibility, and modifying impulsivity.[26] RO5263397 has been reported to inhibit aggression and autism-esque irritability-like behavior induced by serotonin depletion and prenatal exposure to valproic acid.[27][28]

Pharmacokinetics

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RO5263397 has shown favorable pharmacokinetic properties for in vivo use based on its physicochemical properties and preclinical research.[4] It is mainly metabolized by N-glucuronidation in humans.[1][8] UGT2B10 polymorphisms can result in profoundly altered exposure to RO5263397 in humans.[1][7][8][29] Implicated polymorphisms appear to be especially prevalent in people of African descent.[1][7][8][29]

History

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RO5263397 was first described in the scientific literature by 2013.[4] Some findings from a clinical study were reported in 2015.[7][8]

Clinical development

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The drug was under development by Roche for treatment of schizophrenia and reached phase 3 clinical trials for this indication by 2019.[6] The phase 2 results of RO5263397 do not appear to have been disclosed as of this date.[6] However, some findings from one clinical study were published in 2015.[7][8]

See also

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  • RO5073012 – TAAR1 weak partial agonist
  • RO5166017 – TAAR1 partial or full agonist
  • RO5203648 – TAAR1 partial agonist
  • RO5256390 – TAAR1 partial or full 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 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. ^ Schwartz MD, Canales JJ, Zucchi R, Espinoza S, Sukhanov I, Gainetdinov RR (June 2018). "Trace amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases". Expert Opinion on Therapeutic Targets. 22 (6): 513–526. doi:10.1080/14728222.2018.1480723. hdl:11568/930006. PMID 29798691.
  3. ^ a b c "RO 5263397 hydrochloride Supplier". Tocris Bioscience. Retrieved 29 October 2024. RO 5263397 hydrochloride is a potent trace amine 1 (TA1) receptor agonist (EC50 values are 0.12, 35 and 17-85 nM for mouse, rat and human receptors, respectively). Increases wakefulness and reduces REM and NREM sleep duration in wild type mice. Inhibits spontaneous locomotor activity in dopamine transport (DAT) knockout mice.
  4. ^ a b c d e f g h i j k l m n o p q Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, et al. (May 2013). "A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight". Mol Psychiatry. 18 (5): 543–556. doi:10.1038/mp.2012.57. PMID 22641180.
  5. ^ a b c d e f g Espinoza S, Leo D, Sotnikova TD, Shahid M, Kääriäinen TM, Gainetdinov RR (2018). "Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397". Front Pharmacol. 9: 645. doi:10.3389/fphar.2018.00645. PMC 6022153. PMID 29977204. Comparison with a maximal concentration (10 µM) of β-phenylethylamine (PEA), a known TAAR1 full agonist indicated, RO5263397 behaves as a full agonist at the mTAAR1 (EC50: 0.12 nM and Emax: 100%) and partial agonist at the hTAAR1 (EC50: 47 nM and Emax: 82%) as shown in Figures 1C,D, respectively. The data also indicate that RO5263397 shows species related difference with 392-fold higher potency at the mTAAR1 compared to hTAAR1.
  6. ^ a b c Krogmann A, Peters L, von Hardenberg L, Bödeker K, Nöhles VB, Correll CU (August 2019). "Keeping up with the therapeutic advances in schizophrenia: a review of novel and emerging pharmacological entities". CNS Spectr. 24 (S1): 38–69. doi:10.1017/S109285291900124X. PMID 31482779.
  7. ^ a b c d e Dodd S, F Carvalho A, Puri BK, Maes M, Bortolasci CC, Morris G, et al. (January 2021). "Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry?". Neurosci Biobehav Rev. 120: 537–541. doi:10.1016/j.neubiorev.2020.09.028. PMID 33031817. A variable dose study of RO5263397 in 49 healthy male subjects aged 18–45 years, to investigate safety, tolerability, pharmacokinetics, and pharmacodynamics after oral administration, identified one individual subject who showed 136-fold higher exposure and 22-fold higher peak concentration versus all other subjects receiving the same 10-mg dose. Further investigations identified two further individual, all three of African origin, who were poor metabolisers of RO5263397. Clearance of RO5263397 is glucuronidation by the hepatic enzymes UGT1A4 and UGT2B10. Poor metaboliser phenotype for UGT2B10 is common in people of African origin (45%), of moderate frequency in Asians (8%) and uncommon in Caucasians (<1%) (36).
  8. ^ a b c d e f Fowler S, Kletzl H, Finel M, Manevski N, Schmid P, Tuerck D, et al. (February 2015). "A UGT2B10 splicing polymorphism common in african populations may greatly increase drug exposure". J Pharmacol Exp Ther. 352 (2): 358–367. doi:10.1124/jpet.114.220194. PMID 25503386.
  9. ^ a b c d 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.
  10. ^ a b c d e 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.
  11. ^ a b c d Grinchii D, Hoener MC, Khoury T, Dekhtiarenko R, Nejati Bervanlou R, Jezova D, et al. (December 2022). "Effects of acute and chronic administration of trace amine-associated receptor 1 (TAAR1) ligands on in vivo excitability of central monoamine-secreting neurons in rats". Mol Psychiatry. 27 (12): 4861–4868. doi:10.1038/s41380-022-01739-9. PMC 9763099. PMID 36045279.
  12. ^ Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, et al. (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A. 108 (20): 8485–8490. Bibcode:2011PNAS..108.8485R. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407.
  13. ^ a b c d Pei Y, Asif-Malik A, Hoener M, Canales JJ (September 2017). "A partial trace amine-associated receptor 1 agonist exhibits properties consistent with a methamphetamine substitution treatment". Addict Biol. 22 (5): 1246–1256. doi:10.1111/adb.12410. PMID 27193165.
  14. ^ a b c Thorn DA, Jing L, Qiu Y, Gancarz-Kausch AM, Galuska CM, Dietz DM, et al. (September 2014). "Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats". Neuropsychopharmacology. 39 (10): 2309–2316. doi:10.1038/npp.2014.91. PMC 4138753. PMID 24743376.
  15. ^ a b Jing L, Zhang Y, Li JX (October 2014). "Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse-related behavioral indices of methamphetamine in rats". Int J Neuropsychopharmacol. 18 (4): pyu060. doi:10.1093/ijnp/pyu060. PMC 4360231. PMID 25522401.
  16. ^ a b Black SW, Schwartz MD, Chen TM, Hoener MC, Kilduff TS (November 2017). "Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics". Biol Psychiatry. 82 (9): 623–633. doi:10.1016/j.biopsych.2016.10.012. PMC 5395352. PMID 27919403.
  17. ^ a b Goonawardena AV, Morairty SR, Dell R, Orellana GA, Hoener MC, Wallace TL, et al. (July 2019). "Trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in Cynomolgus macaques". Neuropsychopharmacology. 44 (8): 1485–1493. doi:10.1038/s41386-019-0386-8. PMC 6784974. PMID 30954024.
  18. ^ Thorn DA, Zhang C, Zhang Y, Li JX (April 2014). "The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats". Neurosci Lett. 566: 67–71. doi:10.1016/j.neulet.2014.02.024. PMC 3991844. PMID 24561093.
  19. ^ Xue Z, Siemian JN, Johnson BN, Zhang Y, Li JX (February 2018). "Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397". Neuropharmacology. 129: 36–46. doi:10.1016/j.neuropharm.2017.11.012. PMC 6341472. PMID 29128305.
  20. ^ Wu R, Liu J, Wang K, Huang Y, Zhang Y, Li JX (July 2020). "Effects of a trace amine-associated receptor 1 agonist RO 5263397 on ethanol-induced behavioral sensitization". Behav Brain Res. 390: 112641. doi:10.1016/j.bbr.2020.112641. PMC 7286772. PMID 32407821.
  21. ^ Liu J, Seaman R, Johnson B, Wu R, Vu J, Tian J, et al. (February 2021). "Activation of trace amine-associated receptor 1 selectively attenuates the reinforcing effects of morphine". Br J Pharmacol. 178 (4): 933–945. doi:10.1111/bph.15335. PMC 8758336. PMID 33247948.
  22. ^ Schwartz MD, Black SW, Fisher SP, Palmerston JB, Morairty SR, Hoener MC, et al. (May 2017). "Trace Amine-Associated Receptor 1 Regulates Wakefulness and EEG Spectral Composition". Neuropsychopharmacology. 42 (6): 1305–1314. doi:10.1038/npp.2016.216. PMC 5437878. PMID 27658486.
  23. ^ Park S, Heu J, Hoener MC, Kilduff TS (October 2024). "Wakefulness Induced by TAAR1 Partial Agonism in Mice Is Mediated Through Dopaminergic Neurotransmission". Int J Mol Sci. 25 (21): 11351. doi:10.3390/ijms252111351. PMC 11547084. PMID 39518904.
  24. ^ Shabani S, Houlton S, Ghimire B, Tonello D, Reed C, Baba H, et al. (September 2023). "Robust aversive effects of trace amine-associated receptor 1 activation in mice". Neuropsychopharmacology. 48 (10): 1446–1454. doi:10.1038/s41386-023-01578-4. PMC 10425385. PMID 37055488.
  25. ^ Liu J, Wu R, Johnson B, Zhang Y, Zhu Q, Li JX (October 2022). "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology. 239 (10): 3345–3353. doi:10.1007/s00213-022-06222-5. PMID 36056214.
  26. ^ Dorotenko A, Tur M, Dolgorukova A, Bortnikov N, Belozertseva IV, Zvartau EE, et al. (March 2020). "The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats". Cell Mol Neurobiol. 40 (2): 215–228. doi:10.1007/s10571-019-00757-6. PMID 31734895.
  27. ^ Zhukov IS, Alnefeesi Y, Krotova NA, Nemets VV, Demin KA, Karpenko MN, et al. (2024). "Trace amine-associated receptor 1 agonist reduces aggression in brain serotonin-deficient tryptophan hydroxylase 2 knockout rats". Front Psychiatry. 15: 1484925. doi:10.3389/fpsyt.2024.1484925. PMC 11693706. PMID 39748904.
  28. ^ Wang L, Clark EA, Hanratty L, Koblan KS, Foley A, Dedic N, et al. (December 2024). "TAAR1 and 5-HT1B receptor agonists attenuate autism-like irritability and aggression in rats prenatally exposed to valproic acid". Pharmacol Biochem Behav. 245: 173862. doi:10.1016/j.pbb.2024.173862. PMID 39197535.
  29. ^ a b Milani N, Qiu N, Fowler S (March 2023). "Contribution of UGT Enzymes to Human Drug Metabolism Stereoselectivity: A Case Study of Medetomidine, RO5263397, Propranolol, and Testosterone". Drug Metab Dispos. 51 (3): 306–317. doi:10.1124/dmd.122.001024. PMID 36810196.
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