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| Other names | RO-5263397; Ro 5263397; Ro-5263397 |
| Drug class | Trace amine-associated receptor 1 (TAAR1)partial orfull agonist |
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| Formula | C10H11FN2O |
| Molar mass | 194.209 g·mol−1 |
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RO5263397, orRO-5263397, is atrace amine-associated receptor 1 (TAAR1)partial orfull agonist which is used inscientific research.[1][2][3][4][5] It is the most well-studied of all of thesynthetic TAAR1ligands.[1] In addition to its use in research, RO5263397 is or was under development for potential clinical use as a medication.[6][7][8]
RO5263397 is atrace amine-associated receptor 1 (TAAR1)partial agonist tofull agonist.[9][4] ItsEC50Tooltip 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 thecynomolgus monkey TAAR1, and 17 to 85 nM for the human TAAR1 (hTAAR1).[3][9][4][5] Itsintrinsic 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]
| 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 higherpotency at the mTAAR1 compared to the hTAAR1in vitro in one comparative study, although it still activated the hTAAR1 with low-nanomolar potency (EC50 = 0.12 ).[10][5]
RO5263397 has been found to increase thefiring rates ofventral tegmental area (VTA)dopaminergicneurons anddorsal raphe nucleus (DRN)serotonergic neurons in mousebrain slicesex vivo.[1][4][11] This is in contrast to the high-efficacy TAAR1 agonistsp-tyramine,RO5166017, andRO5256390, which inhibit these neurons in such systems, but is similar to the increased firing rates with the TAAR1 antagonistEPPTB, supporting a partially agonistic profile of RO5263397 at the mTAAR1.[1][4][11] RO5263397 can partially anddose-dependently reverse the suppressive effects of RO5256390 on monoaminergic neuron firing in brain slicesex vivo.[11] In contrast to VTA dopaminergic and DRN serotonergic neurons, RO5263397 had no effect onlocus coeruleus (LC)noradrenergic neurons in the system, where the TAAR1 is notably not expressed.[11][12] The effects of RO5263397 on the firing frequencies ofmonoaminergic neurons are absent in TAAR1knockout mice.[4] RO5263397 has been found to fully preventmethamphetamine-induced dopamine release in ratnucleus accumbens core (NAcc) brain slicesex vivo.[10][1][13] Conversely, RO5263397 by itself had no effect on dopamine overflow in rat NAcc slicesex vivo.[13]
RO5263397 alone has no effect onlocomotor activity in rodentsin vivo.[14][15][16] Similarly, RO5263397 did not affect locomotor activity in monkeys.[17] Conversely, RO5263397 has been found to dose-dependently and fully inhibitcocaine-inducedhyperlocomotion in micein vivo.[4] Likewise, it dose-dependently inhibited hyperlocomotion induced by theNMDA receptor antagonistsphencyclidine (PCP) andL-687,414 in micein vivo.[4] The TAAR1full agonist RO5166017 and the high-efficacy TAAR1 partial agonist RO5256390, as well as theantipsychoticolanzapine, 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 indopamine 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 showextrapyramidal-like symptoms likecatalepsy in mice, and instead partially preventedhaloperidol-induced catalepsy, suggesting the potential for an improvedtolerability profile.[4]
RO5263397 has been shown to reducebehavioral sensitization induced by cocaine in mice.[1][18][14] Similarly, it reduces the expression but not development ofconditioned place preference (CPP) by cocaine in mice.[14] Analogously to cocaine, RO5263397 dose-dependently attenuates behavioral sensitization to methamphetamine, reducesself-administration of methamphetamine, and blocks reinstatement ofmethamphetamine-seeking behaviors in rodents.[1][15][13] It also attenuates methamphetamine-inducedimpulsivity in rodents.[1][19] In general, the drug has been found to suppress methamphetamine-, cocaine, andnicotine-inducedstimulant-like andreinforcing effects in animalsin vivo.[10] Analogous findings have been made formorphine andethanol.[1][20][21] RO5263397 has similar effects compared to TAAR1full agonists like RO5256390in vivo in terms of psychostimulant modulation.[10][1] Unlike methamphetamine and othermisused drugs, RO5263397 itself is not self-administered at any dose and shows nomisuse liability.[1][13]
The drug has shownwakefulness-promoting,pro-cognitive-like andantidepressant-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 dopamineD1 andD2 receptors.[23] Similarly to other TAAR1 agonists like RO5166017 and RO5256390, RO5263397 showsaversive effects in animals.[24][25] The drug has been reported to affect measures ofexecutive function in rats, such as increasingattention, decreasingcognitive flexibility, and modifyingimpulsivity.[26] RO5263397 has been reported to inhibitaggression andautism-esqueirritability-like behavior induced by serotonin depletion andprenatal exposure tovalproic acid.[27][28]
RO5263397 has shown favorablepharmacokinetic properties forin vivo use based on itsphysicochemical properties andpreclinical research.[4] It is mainlymetabolized byN-glucuronidation in humans.[1][8]UGT2B10polymorphisms can result in profoundly altered exposure to RO5263397 in humans.[1][7][8][29] Implicated polymorphisms appear to be especially prevalent in people ofAfrican descent.[1][7][8][29]
RO5263397 was first described in thescientific literature by 2013.[4] Some findings from aclinical study were reported in 2015.[7][8]
The drug was under development byRoche for treatment ofschizophrenia and reachedphase 3clinical trials for this indication by 2019.[6] Thephase 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]
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.
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.
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).