Chemistry:RO5256390

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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).[1][2] It is a full agonist of the rat, cynomolgus monkey, and human TAAR1, but a partial agonist of the mouse TAAR1.[1][2]

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.[1][2]

RO5256390 at TAAR1 in different species[2]
Species Affinity (Ki, nM) EC50 (nM) Emax (%)
Mouse 4.4 2–18 68–79%
Rat 2.9 5.1 107%
Monkey 16 16 100%
Human 24 16 98%

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.[1][2] This effect was absent in slices from TAAR1 knockout mice.[1][2] 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.[3] In contrast with acute exposure however, chronic administration of RO5256390 for 14 days increased the excitability of VTA dopaminergic and DRN serotonergic neurons.[3] 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.[1][4]

RO5256390 has been found to fully suppress the hyperlocomotion (a psychostimulant-like effect) induced by cocaine in rodents.[1][2] In addition, it dose-dependently inhibited the hyperlocomotion induced by the NMDA receptor antagonists phencyclidine (PCP) and L-687,414.[1][2] 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.[2] In contrast to classical antipsychotics however, RO5256390 did not produce extrapyramidal-like symptoms in rodents and instead could reduce the catalepsy induced by haloperidol.[2] RO5256390 has been found to dose-dependently inhibit cocaine self-administration and context-triggered cocaine-seeking behavior in rodents.[1][5][6]

RO5256390 shows robust aversive and locomotor-suppressing effects in rodents that are dependent on TAAR1 activation.[7] Similar aversive effects have also been observed with other TAAR1 agonists like RO5263397 and RO5166017.[7][8] 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).[9] In contrast to the TAAR1 partial agonist RO5263397, RO5256390 did not produce antidepressant-like effects in rodents.[2] Conversely however, both agents produced antidepressant-like effects in monkeys.[2]

RO5256390 has been found to produce pro-cognitive effects in rodents and monkeys.[2][10] It has been shown to strongly suppress rapid eye movement (REM) sleep in rodents.[11] On the other hand, it did not promote wakefulness in rodents.[2] RO5256390 has been shown to block compulsive and binge-like eating behavior in rats.[12] For this reason, it is being investigated as a potential drug to treat binge eating disorder.[12]

History

RO5256390 was first described in the scientific literature by 2013.[2]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs 35 (12): 1239–1248. December 2021. doi:10.1007/s40263-021-00871-4. PMID 34766253. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 "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. May 2013. doi:10.1038/mp.2012.57. PMID 22641180. 
  3. ↑ 3.0 3.1 "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. December 2022. doi:10.1038/s41380-022-01739-9. PMID 36045279. 
  4. ↑ "Interaction Between the Trace Amine-Associated Receptor 1 and the Dopamine D2 Receptor Controls Cocaine's Neurochemical Actions". Sci Rep 7 (1): 13901. October 2017. doi:10.1038/s41598-017-14472-z. PMID 29066851. 
  5. ↑ "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. December 2015. doi:10.1016/j.pnpbp.2015.05.014. PMID 26048337. 
  6. ↑ "Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking". Neuropsychopharmacology 39 (10): 2299–2308. September 2014. doi:10.1038/npp.2014.88. PMID 24722355. 
  7. ↑ 7.0 7.1 "Robust aversive effects of trace amine-associated receptor 1 activation in mice". Neuropsychopharmacology 48 (10): 1446–1454. September 2023. doi:10.1038/s41386-023-01578-4. PMID 37055488. 
  8. ↑ "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology (Berl) 239 (10): 3345–3353. October 2022. doi:10.1007/s00213-022-06222-5. PMID 36056214. 
  9. ↑ "Trace amine-associated receptor 1 modulates motor hyperactivity, cognition, and anxiety-like behavior in an animal model of ADHD". Prog Neuropsychopharmacol Biol Psychiatry 117. July 2022. doi:10.1016/j.pnpbp.2022.110555. PMID 35346791. 
  10. ↑ "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. July 2022. doi:10.3390/ijms23147811. PMID 35887159. 
  11. ↑ "Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics". Biol Psychiatry 82 (9): 623–633. November 2017. doi:10.1016/j.biopsych.2016.10.012. PMID 27919403. 
  12. ↑ 12.0 12.1 "The Trace Amine-Associated Receptor 1 Agonist RO5256390 Blocks Compulsive, Binge-like Eating in Rats". Neuropsychopharmacology 42 (7): 1458–1470. June 2017. doi:10.1038/npp.2016.233. PMID 27711047. 



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