RO5203648

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RO5203648 binds to the mouse, rat, cynomolgus monkey, and human TAAR1 all with high affinity (K_i = 0.5–6.8 nM).^[1][2] It is a potent partial agonist in all species (EC₅₀Tooltip half-maximal effective concentration = 4.0 to 31 nM), with an efficacy of 48 to 73% relative to the endogenous TAAR1 agonists β-phenethylamine and tyramine and the TAAR1 full agonist RO5166017.^[1][2][3] RO5203648 is highly selective for the TAAR1, showing ≥130-fold selectivity for the mouse TAAR1 over 149 other targets.^[2][3]

Effects

RO5203648 has been found to increase the firing rate of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo.^[1][5][2] This is in contrast to the TAAR1 full agonist RO5166017, which suppresses their firing rates, but is analogous to the TAAR1 antagonist EPPTB, which dramatically increases their firing rates.^[1][5][2] RO5203648 failed to show these effects in the neurons of TAAR1 knockout mice, indicating that its actions are mediated by interactions with the TAAR1.^[2] RO5203648 alone does not affect electrically evoked dopamine release or reuptake (as measured by tau) in rat nucleus accumbens (NAc) slices ex vivo.^[5][6] Conversely, RO5203648 prevented cocaine-induced dopamine elevations in this system without affecting the dopamine reuptake inhibition of cocaine.^[1][5][6] As such, its inhibition of cocaine's dopaminergic actions is likely to be independent of dopamine transporter (DAT) interactions.^[1][6] RO5203648 did not affect methamphetamine-induced dopamine efflux or reuptake inhibition in rat striatal synaptosomes in vitro.^[7][8][4] However, RO5203648 blunted and delayed methamphetamine-induced dopamine elevations in the NAc in rodents in vivo.^[5][4] Hence, as with cocaine, RO5203648's regulation of methamphetamine's actions appears to be independent of DAT interactions.^[7][5][4]

Some in-vitro studies have suggested that TAAR1 agonism by amphetamines and β-phenethylamine may mediate induction of monoamine release and reuptake inhibition by these agents.^{[9][10][11][12][13][14][14]} However, a subsequent study failed to replicate these findings under similar conditions.^[7] In addition, as previously described, RO5203648 did not affect methamphetamine-induced dopamine release and reuptake inhibition in synaptosomes in vitro.^[7][8][5][4] The dopamine elevations and psychostimulant-like effects of amphetamines are not only preserved but are actually augmented in TAAR1 knockout mice in vivo.^{[9][8][15][16]} Concordant in-vivo findings have been made with amphetamines combined with TAAR1 agonists and antagonists as well as with TAAR1 overexpression.^[8] It appears that TAAR1 agonism by amphetamines, such as amphetamine, methamphetamine, and MDMA, auto-inhibits their monoaminergic effects.^[17][18][19] Conversely, most cathinones lack TAAR1 agonism, and this might enhance their effects compared to amphetamines.^[18][20]

RO5203648 does not significantly affect basal locomotion.^[2] Conversely, the drug has been found to dose-dependently suppress cocaine-induced hyperlocomotion in mice and rats, whereas it only suppressed dextroamphetamine-induced hyperactivity at a high dose in rats and did not affect dextroamphetamine-induced hyperlocomotion in mice.^{[1][21][5][2]} RO5203648 reduced early but potentiated late hyperlocomotion induced by methamphetamine.^[1][4] With chronic administration of RO5203648 and methamphetamine, RO5203648 dose-dependently and progressively decreased methamphetamine-induced hyperlocomotion.^[1][4] TAAR1 full agonists like RO5166017 and RO5256390 also suppress psychostimulant-induced hyperlocomotion.^[21] RO5203648 suppressed spontaneous hyperactivity in a novel environment in dopamine transporter (DAT) knockout mice, similarly to antipsychotics like haloperidol and olanzapine.^[2][22] RO5203648 has also been found to suppress hyperlocomotion induced by the NMDA receptor antagonist L-687,414 or in genetically modified mice with a hypoactive NMDA receptor.^[1][2] The effects of RO5203648 on hyperdopaminergic- and hypoglutamatergic-mediated hyperlocomotion are similar to those of the TAAR1 full agonist RO5166017.^[21][2]

The drug has shown anti-cataleptic, pro-cognitive, antipsychotic-like, antidepressant-like, anxiolytic-like, anti-addictive, and wakefulness-promoting effects in animals.^{[2][3][1][6][23]} RO5203648, as well as the TAAR1 full agonist RO5256390, have been found to suppress cocaine and methamphetamine self-administration, and hence presumably their rewarding and reinforcing effects.^[1][5][23] RO5203648 also blocked methamphetamine-induced locomotor sensitization, but cross-sensitized with methamphetamine at the highest dose.^[5][4] RO5203648 by itself is not self-administered in animals, suggesting that it lacks reinforcing effects and misuse liability of its own.^[21][4]