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RO-5256390

Clinical data
Drug class	Trace amine-associated receptor 1 (TAAR1) partial or full agonist
Identifiers
IUPAC name (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
CAS Number	1043495-96-0
PubChem CID	24963286
ChemSpider	34959936
ChEMBL	ChEMBL3684869
Chemical and physical data
Formula	C13H18N2O
Molar mass	218.300 g·mol
3D model (JSmol)	Interactive image
SMILES NC1=N(C(C2=CC=CC=C2)CC)CO1
InChI InChI=1S/C13H18N2O/c1-2-10(11-6-4-3-5-7-11)8-12-9-16-13(14)15-12/h3-7,10,12H,2,8-9H2,1H3,(H2,14,15)/t10-,12-/m0/s1 Key:IXDKFUBXESWHSL-JQWIXIFHSA-N

RO5256390 or RO-5256390 is a drug developed by Hoffmann-La Roche which acts as an agonist for the trace amine associated receptor 1 (TAAR1). It is a full agonist of the rat, cynomolgus monkey, and human TAAR1, but a partial agonist of the mouse TAAR1.

Pharmacology

Pharmacodynamics

Actions

RO5256390 is a full agonist of the rat, cynomolgus monkey, and human TAAR1, but a high-efficacy partial agonist of the mouse TAAR1.

Effects

RO5256390 has been found to suppress the firing rates of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo. This effect was absent in slices from TAAR1 knockout mice. Similarly, acute RO5256390 suppressed VTA dopaminergic and DRN serotonergic neuronal excitability in rats in vivo, whereas the excitability of locus coeruleus (LC) noradrenergic neurons was unaffected. In contrast with acute exposure however, chronic administration of RO5256390 for 14 days increased the excitability of VTA dopaminergic and DRN serotonergic neurons. The drug has been found to dose-dependently block cocaine-induced inhibition of dopamine clearance (reuptake inhibition) in rat nucleus accumbens (NAc) slices ex vivo whilst having no effect on dopamine clearance by itself.

RO5256390 has been found to fully suppress the hyperlocomotion (a psychostimulant-like effect) induced by cocaine in rodents. In addition, it dose-dependently inhibited the hyperlocomotion induced by the NMDA receptor antagonists phencyclidine (PCP) and L-687,414. RO5256390 is said to produce a brain activity pattern similar to that of the antipsychotic olanzapine in rodents and hence is presumed to have antipsychotic-like properties. In contrast to classical antipsychotics however, RO5256390 did not produce extrapyramidal-like symptoms in rodents and instead could reduce the catalepsy induced by haloperidol. RO5256390 has been found to dose-dependently inhibit cocaine self-administration and context-triggered cocaine-seeking behavior in rodents.

RO5256390 shows robust aversive and locomotor-suppressing effects in rodents that are dependent on TAAR1 activation. Similar aversive effects have also been observed with other TAAR1 agonists like RO5263397 and RO5166017. RO5256390 has been shown to decrease motor hyperactivity, novelty-induced locomotor activity, and induce anxiolytic-like effects in the spontaneously hypertensive rat (SHR), a rodent model of attention deficit hyperactivity disorder (ADHD). In contrast to the TAAR1 partial agonist RO5263397, RO5256390 did not produce antidepressant-like effects in rodents. Conversely however, both agents produced antidepressant-like effects in monkeys.

RO5256390 has been found to produce pro-cognitive effects in rodents and monkeys. It has been shown to strongly suppress rapid eye movement (REM) sleep in rodents. On the other hand, it did not promote wakefulness in rodents. RO5256390 has been shown to block compulsive and binge-like eating behavior in rats. For this reason, it is being investigated as a potential drug to treat binge eating disorder.

History

RO5256390 was first described in the scientific literature by 2013.

See also

• RO5073012 – TAAR1 weak partial agonist
• RO5166017 – TAAR1 partial or full agonist
• RO5203648 – TAAR1 partial agonist
• RO5263397 – TAAR1 partial agonist
• EPPTB – TAAR1 antagonist/inverse agonist

References

1. ^ 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. ^ Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC (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.
3. ^ Grinchii D, Hoener MC, Khoury T, Dekhtiarenko R, Nejati Bervanlou R, Jezova D, Dremencov E (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.
4. Asif-Malik A, Hoener MC, Canales JJ (October 2017). "Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine's Neurochemical Actions". Sci Rep. 7 (1): 13901. doi:10.1038/s41598-017-14472-z. PMC 5655641. PMID 29066851.
5. 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.
6. 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.
7. ^ Shabani S, Houlton S, Ghimire B, Tonello D, Reed C, Baba H, Aldrich S, Phillips TJ (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.
8. Liu J, Wu R, Johnson B, Zhang Y, Zhu Q, Li JX (October 2022). "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology (Berl). 239 (10): 3345–3353. doi:10.1007/s00213-022-06222-5. PMID 36056214.
9. Raony Í, Domith I, Lourenco MV, Paes-de-Carvalho R, Pandolfo P (July 2022). "Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD". Prog Neuropsychopharmacol Biol Psychiatry. 117: 110555. doi:10.1016/j.pnpbp.2022.110555. PMID 35346791.
10. Leo D, Targa G, Espinoza S, Villers A, Gainetdinov RR, Ris L (July 2022). "Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease". Int J Mol Sci. 23 (14): 7811. doi:10.3390/ijms23147811. PMC 9318502. PMID 35887159.
11. 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.
12. ^ Ferragud A, Howell AD, Moore CF, Ta TL, Hoener MC, Sabino V, Cottone P (June 2017). "The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats". Neuropsychopharmacology. 42 (7): 1458–1470. doi:10.1038/npp.2016.233. PMC 5436108. PMID 27711047.

• Amines
• Oxazolines
• TAAR1 agonists
• TAAR1 antagonists