RO5256390

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RO-5256390
Clinical data
Drug classTrace amine-associated receptor 1 (TAAR1) partial or full agonist
Identifiers
  • (S)-4-((S)-2-phenyl-butyl)-4,5-dihydro-oxazol-2-ylamine
CAS Number
PubChem CID
ChemSpider
ChEMBL
E number{{#property:P628}}
CompTox Dashboard (EPA)
  • {{#property:P3117}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 29: attempt to index field 'wikibase' (a nil value).
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 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

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Pharmacodynamics

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Actions

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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) EC50Tooltip half-maximal effective concentration (nM) EmaxTooltip maximal efficacy (%)
Mouse 4.4 2–18 68–79%
Rat 2.9 5.1 107%
Monkey 16 16 100%
Human 24 16 98%

Effects

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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

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

See also

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References

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