RO5203648

Last updated

RO5203648
RO5203648.svg
Clinical data
Other namesRO-5203648
Drug class Trace amine-associated receptor 1 (TAAR1) partial agonist
Identifiers
  • (4S)-4-(3,4-dichlorophenyl)-4,5-dihydro-1,3-oxazol-2-amine
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C9H8Cl2N2O
Molar mass 231.08 g·mol−1
3D model (JSmol)
  • C1[C@@H](N=C(O1)N)C2=CC(=C(C=C2)Cl)Cl
  • InChI=1S/C9H8Cl2N2O/c10-6-2-1-5(3-7(6)11)8-4-14-9(12)13-8/h1-3,8H,4H2,(H2,12,13)/t8-/m1/s1
  • Key:HGGPGNSCBBAGJN-MRVPVSSYSA-N

RO5203648 is a trace amine-associated receptor 1 (TAAR1) partial agonist. [1] [2] [3] It is a potent and highly selective partial agonist of both rodent and primate TAAR1. [2] [3] The drug suppresses the effects of psychostimulants like cocaine and methamphetamine. [1] [2] It also produces a variety of other behavioral effects, such as antidepressant-like, antipsychotic-like, and antiaddictive effects. [1] [2] [4] Research with RO5203648 has led to interest in TAAR1 agonists for potential treatment of drug addiction. [1] RO5203648 itself was not developed for potential medical use due to poor expected human pharmacokinetics. [3]

Contents

Pharmacology

Pharmacodynamics

Actions

RO5203648 binds to the mouse, rat, cynomolgus monkey, and human TAAR1 all with high affinity (Ki = 0.5–6.8 nM). [1] [2] It is a potent partial agonist in all species (EC50 Tooltip 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]

RO5203648 at TAAR1 in different species [2] [3] [1]
Species Affinity (Ki, nM) EC50 Tooltip half-maximal effective concentration (nM) Emax Tooltip maximal efficacy (%)
Mouse 0.52.1–4.048–71%
Rat 1.06.859%
Monkey 2.63169%
Human 6.83073%

Effects

RO5203648 has been found to increase the firing rate of ventral tegmental area (VTA) dopaminergic neurons and raphe nucleus serotonergic neurons in vitro . [1] [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] [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] In contrast to basal dopaminergic signaling, the drug has been found to reduce cocaine- and methamphetamine-induced dopamine elevations in the nucleus accumbens in rats. [1] [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. [6] [7] [8] [9] [10] [11] [11] However, a subsequent study failed to replicate these findings under similar conditions. [12] In addition, RO5203648 did not affect methamphetamine-induced dopamine release and reuptake inhibition in striatal brain synaptosomes in vitro . [12] [4] The dopamine elevations and psychostimulant-like effects of amphetamines are not only preserved but are actually augmented in TAAR1 knockout mice in vivo . [6] [13] [14] [15] Concordant in-vivo findings have been made with amphetamines combined with TAAR1 agonists and antagonists as well as with TAAR1 overexpression. [13] It appears that TAAR1 agonism by amphetamines, such as amphetamine, methamphetamine, and MDMA, auto-inhibits their monoaminergic effects. [16] [17] [18] Conversely, most cathinones lack TAAR1 agonism. [17] [19]

RO5203648 does not significantly affect basal locomotion. [2] Conversely, the drug has been found to suppress cocaine-induced hyperlocomotion in mice and rats, whereas it only suppressed dextroamphetamine-induced hyperactivity in rats but not in mice. [1] [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] RO5203648 suppressed spontaneous hyperactivity in a novel environment in dopamine transporter (DAT) knockout mice, similarly to antipsychotics like haloperidol and olanzapine. [2] [20] 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. [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] [5] [21] 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] [21] RO5203648 also blocked methamphetamine-induced locomotor sensitization, but cross-sensitized with methamphetamine at the highest dose. [4]

Pharmacokinetics

RO5203648 showed favorable pharmacokinetics orally and intravenously in mice, rats, and monkeys. [2] However, it was found to be very rapidly metabolized in human hepatocytes in vitro . [3]

Chemistry

In terms of chemical structure, RO5203648 is a 2-aminooxazoline derivative. [3] [22] This group also includes a number of other selective TAAR1 ligands, including the near-full agonist RO5166017, the full agonist RO5256390, and the partial agonist RO5263397. [3] RO5203648 is also very closely structurally related to the monoamine releasing agents and psychostimulants aminorex and clominorex. [22]

History

RO5203648 was first described by 2012. [2] It was the first selective TAAR1 partial agonist to be developed. [1] [2] [3] The drug followed the first TAAR1 antagonist EPPTB and the first TAAR1 full agonist RO5166017. [2] It was under investigation for potential clinical use in humans, but showed indication of very rapid human metabolism in vitro . [3] As a result, it was deselected from development, and other compounds, such as the TAAR1 partial agonist RO5263397, were pursued instead. [3]

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

<span class="mw-page-title-main">Tryptamine</span> Metabolite of the amino acid tryptophan

Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon. The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter is a membrane-spanning protein coded for in humans by the SLC6A3 gene, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

An autoreceptor is a type of receptor located in the membranes of nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. Similarly, a heteroreceptor is sensitive to neurotransmitters and hormones that are not released by the cell on which it sits. A given receptor can act as either an autoreceptor or a heteroreceptor, depending upon the type of transmitter released by the cell on which it is embedded.

<span class="mw-page-title-main">Levmetamfetamine</span> Topical nasal decongestant

Levmetamfetamine, also known as l-desoxyephedrine or levomethamphetamine, and commonly sold under the brand name Vicks VapoInhaler among others, is an optical isomer of methamphetamine primarily used as a topical nasal decongestant. It is used to treat nasal congestion from allergies and the common cold. It was first used medically as decongestant beginning in 1958 and has been used for such purposes, primarily in the United States, since then.

<span class="mw-page-title-main">Vesicular monoamine transporter 2</span> Mammalian protein found in Homo sapiens

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">Lobeline</span> Chemical compound

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<span class="mw-page-title-main">Naphthylaminopropane</span> Chemical compound

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<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitters and hence enhanced signaling by those neurotransmitters. The monoamine neurotransmitters include serotonin, norepinephrine, and dopamine; MRAs can induce the release of one or more of these neurotransmitters.

<span class="mw-page-title-main">Norepinephrine releasing agent</span> Catecholaminergic type of drug

A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into the synapse. This in turn leads to increased extracellular concentrations of norepinephrine and epinephrine therefore an increase in adrenergic neurotransmission.

<span class="mw-page-title-main">RTI-113</span> Chemical compound

RTI(-4229)-113 is a stimulant drug which acts as a potent and fully selective dopamine reuptake inhibitor (DRI). It has been suggested as a possible substitute drug for the treatment of cocaine addiction. "RTI-113 has properties that make it an ideal medication for cocaine abusers, such as an equivalent efficacy, a higher potency, and a longer duration of action as compared to cocaine." Replacing the methyl ester in RTI-31 with a phenyl ester makes the resultant RTI-113 fully DAT specific. RTI-113 is a particularly relevant phenyltropane cocaine analog that has been tested on squirrel monkeys. RTI-113 has also been tested against cocaine in self-administration studies for DAT occupancy by PET on awake rhesus monkeys. The efficacy of cocaine analogs to elicit self-administration is closely related to the rate at which they are administered. Slower onset of action analogs are less likely to function as positive reinforcers than analogues that have a faster rate of onset.

<span class="mw-page-title-main">RO5166017</span> Chemical compound

RO5166017, or RO-5166017, is a drug developed by Hoffmann-La Roche which acts as a potent and selective agonist for the trace amine-associated receptor 1 (TAAR1), with no significant activity at other targets. It is a partial agonist or near-full agonist depending on the species.

<span class="mw-page-title-main">EPPTB</span> Chemical compound

EPPTB, also known as RO5212773 or RO-5212773, is a drug developed by Hoffmann-La Roche which acts as a potent and selective antagonist or inverse agonist of the trace amine-associated receptor 1 (TAAR1). The drug was the first selective antagonist developed for the TAAR1. It is a potent agonist of the mouse and rat TAAR1, but is dramatically less potent as an agonist of the human TAAR1. EPPTB has been used in scientific research to demonstrate an important role for TAAR1 in regulation of dopaminergic signaling in the limbic system.

A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamine transporters (MATs), which include the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT). This in turn results in an increase in the synaptic concentrations of one or more of these neurotransmitters and therefore an increase in monoaminergic neurotransmission.

<span class="mw-page-title-main">Monoaminergic activity enhancer</span> Class of compounds in the nervous system

Monoaminergic activity enhancers (MAE), also known as catecholaminergic/serotonergic activity enhancers (CAE/SAE), are a class of drugs that enhance the action potential-evoked release of monoamine neurotransmitters in the nervous system. MAEs are distinct from monoamine releasing agents (MRAs) like amphetamine and fenfluramine in that they do not induce the release of monoamines from synaptic vesicles but rather potentiate only nerve impulse propagation-mediated monoamine release. That is, MAEs increase the amounts of monoamine neurotransmitters released by neurons per electrical impulse.

<span class="mw-page-title-main">RO5263397</span> TAAR1 agonist

RO5263397, or RO-5263397, is a trace amine-associated receptor 1 (TAAR1) partial agonist which is used in scientific research.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Wu 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.
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  4. 1 2 3 4 5 6 Cotter R, Pei Y, Mus L, Harmeier A, Gainetdinov RR, Hoener MC, et al. (2015). "The trace amine-associated receptor 1 modulates methamphetamine's neurochemical and behavioral effects". Front Neurosci. 9: 39. doi: 10.3389/fnins.2015.00039 . PMC   4327507 . PMID   25762894. In the synaptosomal preparation RO5203648 did not affect METH-induced striatal DA release and DA uptake inhibition, suggesting that RO5203648 regulation of METH's behavioral effects is unlikely to depend on direct, local actions at the DAT. As previously indicated, the in vivo microdialysis data revealed transient but significant reduction in METH-induced DA overflow following RO5203648 treatment.
  5. 1 2 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.
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  7. ↑ Grandy DK, Miller GM, Li JX (February 2016). ""TAARgeting Addiction"--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference". Drug Alcohol Depend. 159: 9–16. doi:10.1016/j.drugalcdep.2015.11.014. PMC   4724540 . PMID   26644139.
  8. ↑ Xie Z, Miller GM (April 2007). "Trace amine-associated receptor 1 is a modulator of the dopamine transporter". J Pharmacol Exp Ther. 321 (1): 128–136. doi:10.1124/jpet.106.117382. PMID   17234899.
  9. ↑ Xie Z, Miller GM (July 2009). "A receptor mechanism for methamphetamine action in dopamine transporter regulation in brain". J Pharmacol Exp Ther. 330 (1): 316–325. doi:10.1124/jpet.109.153775. PMC   2700171 . PMID   19364908.
  10. ↑ Xie Z, Miller GM (May 2008). "Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain". J Pharmacol Exp Ther. 325 (2): 617–628. doi:10.1124/jpet.107.134247. PMID   18182557.
  11. 1 2 Miller GM, Xie Z (2010). "Trace amine associated receptor 1 mediates methamphetamine effects on monoamine transporter function". The FASEB Journal. 24 (S1). doi: 10.1096/fasebj.24.1_supplement.578.5 . ISSN   0892-6638.
  12. 1 2 Miner NB, Phillips TJ, Janowsky A (October 2019). "The Role of Biogenic Amine Transporters in Trace Amine-Associated Receptor 1 Regulation of Methamphetamine-Induced Neurotoxicity". J Pharmacol Exp Ther. 371 (1): 36–44. doi:10.1124/jpet.119.258970. PMC   6750185 . PMID   31320495. We were unable to replicate the results of Xie and Miller (2009) under similar in vitro conditions (Fig. 3). There was no difference in IC50 values for [3H]DA uptake inhibition by MA between synaptosomes from Taar1 WT and KO mice. [...] our results do not support an earlier hypothesis that TAAR1 modulates DAT (Xie and Miller, 2007, 2009; Xie et al., 2008b), as there was no evidence of an interaction under conditions described above. Recent reports support our findings that the DAT is unaffected by TAAR1. Coadministration of MA and the TAAR1 partial agonist RO523648 did not alter [3H]DA uptake and release in striatal synaptosomes in rats (Cotter et al., 2015). [...] Given the lack of interaction, DAT is an improbable mediator of TAAR1 regulation of MA-induced neurotoxicity. [...] activation of TAAR1 did not modulate in vitro MA-impairment of DAT function or DAT expression. As TAAR1 activation did not alter the function or expression of DAT in whole synaptosomes [...], these results indicate TAAR1 does not interact with these transporters on the plasma membrane [...]
  13. 1 2 Liu J, Wu R, Li JX (March 2020). "TAAR1 and Psychostimulant Addiction". Cell Mol Neurobiol. 40 (2): 229–238. doi:10.1007/s10571-020-00792-8. PMC   7845786 . PMID   31974906.
  14. ↑ Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, et al. (March 2008). "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther. 324 (3): 948–956. doi:10.1124/jpet.107.132647. PMID   18083911.
  15. ↑ Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (April 2012). "Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1". Pharmacol Biochem Behav. 101 (2): 201–207. doi:10.1016/j.pbb.2011.10.025. PMC   3288391 . PMID   22079347.
  16. ↑ Espinoza S, Gainetdinov RR (2014). "Neuronal Functions and Emerging Pharmacology of TAAR1". Taste and Smell. Vol. 23. Cham: Springer International Publishing. pp. 175–194. doi:10.1007/7355_2014_78. ISBN   978-3-319-48925-4. Interestingly, the concentrations of amphetamine found to be necessary to activate TAAR1 are in line with what was found in drug abusers [3, 51, 52]. Thus, it is likely that some of the effects produced by amphetamines could be mediated by TAAR1. Indeed, in a study in mice, MDMA effects were found to be mediated in part by TAAR1, in a sense that MDMA auto-inhibits its neurochemical and functional actions [46]. Based on this and other studies (see other section), it has been suggested that TAAR1 could play a role in reward mechanisms and that amphetamine activity on TAAR1 counteracts their known behavioral and neurochemical effects mediated via dopamine neurotransmission.
  17. 1 2 Kuropka P, Zawadzki M, Szpot P (May 2023). "A narrative review of the neuropharmacology of synthetic cathinones-Popular alternatives to classical drugs of abuse". Hum Psychopharmacol. 38 (3): e2866. doi:10.1002/hup.2866. PMID   36866677. Another feature that distinguishes [synthetic cathinones (SCs)] from amphetamines is their negligible interaction with the trace amine associated receptor 1 (TAAR1). Activation of this receptor reduces the activity of dopaminergic neurones, thereby reducing psychostimulatory effects and addictive potential (Miller, 2011; Simmler et al., 2016). Amphetamines are potent agonists of this receptor, making them likely to self‐inhibit their stimulating effects. In contrast, SCs show negligible activity towards TAAR1 (Kolaczynska et al., 2021; Rickli et al., 2015; Simmler et al., 2014, 2016).
  18. ↑ Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, et al. (November 2011). "Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)". J Neurosci. 31 (47): 16928–16940. doi:10.1523/JNEUROSCI.2502-11.2011. PMC   6623861 . PMID   22114263.
  19. ↑ Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME (April 2016). "In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1". J Pharmacol Exp Ther. 357 (1): 134–144. doi:10.1124/jpet.115.229765. PMID   26791601.
  20. ↑ Leo D, Sukhanov I, Zoratto F, Illiano P, Caffino L, Sanna F, et al. (February 2018). "Pronounced Hyperactivity, Cognitive Dysfunctions, and BDNF Dysregulation in Dopamine Transporter Knock-out Rats". J Neurosci. 38 (8): 1959–1972. doi:10.1523/JNEUROSCI.1931-17.2018. PMC   5824739 . PMID   29348190.
  21. 1 2 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.
  22. 1 2 "(S)-4-(3,4-Dichlorophenyl)-4,5-dihydrooxazol-2-amine". PubChem. Retrieved 18 December 2024.


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