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RO5256390

From Wikipedia, the free encyclopedia
Chemical compound
Pharmaceutical compound
RO-5256390
Clinical data
Drug classTrace amine-associated receptor 1 (TAAR1)partial orfull agonist
Identifiers
  • (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
CAS Number
PubChemCID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC13H18N2O
Molar mass218.300 g·mol−1
3D model (JSmol)
  • NC1=N[C@@H](C[C@@H](C2=CC=CC=C2)CC)CO1
  • 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 orRO-5256390 is a drug developed byHoffmann-La Roche which acts as anagonist for thetrace amine associated receptor 1 (TAAR1).[1][2] It is afull agonist of the rat, cynomolgus monkey, and human TAAR1, but apartial agonist of the mouse TAAR1.[1][2]

Pharmacology

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Pharmacodynamics

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Actions

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RO5256390 is afull agonist of the rat, cynomolgus monkey, and human TAAR1, but a high-efficacypartial agonist of the mouse TAAR1.[1][2]

RO5256390 at TAAR1 in different species[2]
SpeciesAffinity (Ki, nM)EC50Tooltip half-maximal effective concentration (nM)EmaxTooltip maximal efficacy (%)
Mouse4.42–1868–79%
Rat2.95.1107%
Monkey1616100%
Human241698%

Effects

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RO5256390 has been found to suppress thefiring rates ofventral tegmental area (VTA)dopaminergicneurons anddorsal raphe nucleus (DRN)serotonergic neurons in mousebrain slicesex vivo.[1][2] This effect was absent in slices from TAAR1knockout mice.[1][2] Similarly, acute RO5256390 suppressed VTA dopaminergic and DRN serotonergic neuronal excitability in ratsin vivo, whereas the excitability oflocus 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 todose-dependently blockcocaine-induced inhibition of dopamineclearance (reuptake inhibition) in ratnucleus accumbens (NAc) slicesex vivo whilst having no effect on dopamine clearance by itself.[1][4]

RO5256390 has been found to fully suppress thehyperlocomotion (apsychostimulant-like effect) induced bycocaine in rodents.[1][2] In addition, it dose-dependently inhibited the hyperlocomotion induced by theNMDA receptor antagonistsphencyclidine (PCP) andL-687,414.[1][2] RO5256390 is said to produce a brain activity pattern similar to that of theantipsychoticolanzapine in rodents and hence is presumed to have antipsychotic-like properties.[2] In contrast to classical antipsychotics however, RO5256390 did not produceextrapyramidal-like symptoms in rodents and instead could reduce thecatalepsy induced byhaloperidol.[2] RO5256390 has been found to dose-dependently inhibit cocaineself-administration and context-triggeredcocaine-seeking behavior in rodents.[1][5][6]

RO5256390 shows robustaversive andlocomotor-suppressing effects in rodents that are dependent on TAAR1 activation.[7] Similar aversive effects have also been observed with other TAAR1 agonists likeRO5263397 andRO5166017.[7][8] RO5256390 has been shown to decreasemotor hyperactivity,novelty-inducedlocomotor activity, and induceanxiolytic-like effects in thespontaneously hypertensive rat (SHR), arodent model ofattention deficit hyperactivity disorder (ADHD).[9] In contrast to the TAAR1 partial agonist RO5263397, RO5256390 did not produceantidepressant-like effects in rodents.[2] Conversely however, both agents produced antidepressant-like effects in monkeys.[2]

RO5256390 has been found to producepro-cognitive effects in rodents and monkeys.[2][10] It has been shown to strongly suppressrapid eye movement (REM)sleep in rodents.[11] On the other hand, it did notpromote wakefulness in rodents.[2] RO5256390 has been shown to blockcompulsive andbinge-like eating behavior in rats.[12] For this reason, it is being investigated as a potential drug to treatbinge eating disorder.[12]

History

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

See also

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References

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  1. ^abcdefghiWu 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. ^abcdefghijklmnoRevel 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. ^abGrinchii 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. ^abShabani 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.PMC 11956827.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. ^abFerragud 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.
TAAR1Tooltip Trace amine-associated receptor 1
Agonists
Endogenous
Exogenous
Antagonists
Inverse agonists
TAAR5Tooltip Trace amine-associated receptor 5
Agonists
Inverse agonists
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.
See also:Receptor/signaling modulators
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