Chemistry:RO5166017

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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.[1][2][3] It is a partial agonist or near-full agonist depending on the species.[4][3]

The drug is important for the study of the TAAR1 receptor, as while numerous other compounds are known which act as TAAR1 agonists, such as methamphetamine, MDMA, and 3-iodothyronamine, all previously known TAAR1 agonists are either weak and rapidly metabolized (endogenous ligands), or have strong pharmacological activity at other targets (amphetamines, thyronamines), making it very difficult to assess which effects are due to TAAR1 activation. The discovery of RO-5166017 allows purely TAAR1 mediated effects to be studied.

Pharmacology

Pharmacodynamics

Actions

RO5166017 is a partial agonist or near-full agonist of the TAAR1 depending on the species examined.[4][3] Its EC50 values are 3.3 to 8.0 nM for the mouse TAAR1 (mTAAR1), 14 nM for the rat TAAR1 (rTAAR1), 97 nM for the cynomolgus monkey TAAR1, and 55 nM for the human TAAR1.[4][3] Its Emax values are 65 to 72% for the mTAAR1, 90% for the rTAAR1, 81% for the cynomolgus monkey TAAR1, and 95% for the hTAAR1.[4][3] RO5166017 is selective for the TAAR1 over a large array of other targets.[3]

RO5166017 at TAAR1 in different species[4][3]
Species Affinity (Ki, nM) EC50 (nM) Emax (%)
Mouse 1.9 3.3–8.0 65–72%
Rat 2.7 14 90%
Monkey 24 97 81%
Human 31 55 95%

Effects

RO5166017 has been found to inhibit the firing rates of ventral tegmental area (VTA) dopaminergic neurons and dorsal raphe nucleus (DRN) serotonergic neurons in mouse brain slices ex vivo.[1][5][3][6] Conversely, it had no effect on the firing rates of locus coeruleus (LC) noradrenergic neurons, an area where TAAR1 is not expressed.[7][3] The effects of RO5166017 on monoaminergic neuron firing frequencies were absent in TAAR1 knockout mice and could be reversed by the TAAR1 antagonist RTI-7470-44, indicating that they were mediated by TAAR1 activation.[1][3][6] Similar effects have been observed with the TAAR1 full agonist p-tyramine.[8][3][9][10] Likewise, RO5166017 inhibited electrically evoked dopamine release in dorsal striatum (DStr) and nucleus accumbens (NAc) mouse brain slices ex vivo.[11][12][13] Inhibition of NAc dopamine overflow by RO5166017 could be reversed by the TAAR1 antagonist EPPTB.[12][13] Neither RO5166017 nor EPPTB had any effect on measures of dopamine reuptake or clearance (tau and half-life) in dopaminergic brain slices ex vivo.[14][13]

Previous in-vitro studies found that TAAR1 could activate several signaling cascades including PKA, PKC, ERK1/2, and CREB.[15] However, RO5166017 did not affect these signaling pathways, nor GSK3β, in rats in vivo, and instead selectively and TAAR1-dependently inhibited CaMKIIα activity in the NAc.[15]

In animal studies, RO5166017 has little or no effect on locomotor activity itself.[3][15] In contrast to psychostimulants like amphetamine and cocaine, it does not show stimulant-like or rewarding effects across a broad dose range.[16] The drug dose-dependently suppresses cocaine-induced hyperlocomotion and stereotypies.[1][5][14][8][3] Likewise, it suppresses hyperlocomotion induced by the NMDA receptor antagonist L-687,414.[1][3] In dopamine transporter (DAT) knockout mice, which show spontaneous hyperactivity in novel environments, RO5166017 suppresses hyperlocomotion.[14][8][3] These effects of RO5166017 are similar to those of antipsychotics like haloperidol and olanzapine.[3] They are absent in TAAR1 knockout mice, indicating that they are mediated by the TAAR1.[5][3] These findings indicate that RO5166017 has antipsychotic-like effects.[3]

RO5166017 has been found to inhibit expression, though not reconsolidation or retention, of cocaine-induced conditioned place preference (CPP) in mice.[1][5][17] Systemic administration or microinjection of RO5166017 into various brain regions has been found to inhibit other cocaine-induced relapse-like behaviors in rodents as well.[1][18][15] As with cocaine, RO5166017 has been found to inhibit nicotine-induced dopamine release in the NAc and to reduce nicotine intake and relapse-like behaviors.[1][5][19]

RO5166017 has been shown shown to prevent stress-induced hyperthermia in rodents.[3] It has shown robust aversive effects in rodents, similarly to other TAAR1 agonists like RO5256390 and RO5263397.[20][21] RO5166017 has shown anxiolytic-like effects in mice.[3] It has been found to produce anti-impulsivity-like effects in mice.[5][22] The drug has been found to augment 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurodegeneration in mice and to counteract levodopa-induced contralateral rotations and dyskinesia.[4][23] RO5166017 has shown anti-post-traumatic stress disorder (PTSD)-like effects in rodents.[24]

Pharmacokinetics

RO5166017 has shown favorable pharmacokinetic properties for in vivo use.[1][3]

History

RO5166017 was first described in the scientific literature by 2011.[3] It was the first selective TAAR1 agonist to be discovered.[1][25]

See also

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 "Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders". CNS Drugs 35 (12): 1239–1248. December 2021. doi:10.1007/s40263-021-00871-4. PMID 34766253. 
  2. ↑ "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. May 2013. doi:10.1038/mp.2012.57. PMID 22641180. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 3.20 3.21 "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A 108 (20): 8485–8490. May 2011. doi:10.1073/pnas.1103029108. PMID 21525407. Bibcode: 2011PNAS..108.8485R. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 "Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges". Pharmacol Ther 180: 161–180. December 2017. doi:10.1016/j.pharmthera.2017.07.002. PMID 28723415. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "TAAR1 and Psychostimulant Addiction". Cell Mol Neurobiol 40 (2): 229–238. March 2020. doi:10.1007/s10571-020-00792-8. PMID 31974906. 
  6. ↑ 6.0 6.1 "Identification of a Potent Human Trace Amine-Associated Receptor 1 Antagonist". ACS Chem Neurosci 13 (7): 1082–1095. April 2022. doi:10.1021/acschemneuro.2c00086. PMID 35325532. 
  7. ↑ "Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies". Int J Mol Sci 22 (24): 13185. December 2021. doi:10.3390/ijms222413185. PMID 34947997. 
  8. ↑ 8.0 8.1 8.2 "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur J Pharmacol 761: 345–352. August 2015. doi:10.1016/j.ejphar.2015.06.019. PMID 26092759. 
  9. ↑ "Trace amine-associated receptor 1 modulates dopaminergic activity". J Pharmacol Exp Ther 324 (3): 948–956. March 2008. doi:10.1124/jpet.107.132647. PMID 18083911. 
  10. ↑ "The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system". Proc Natl Acad Sci U S A 106 (47): 20081–6. November 2009. doi:10.1073/pnas.0906522106. PMID 19892733. Bibcode: 2009PNAS..10620081B. 
  11. ↑ "Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications". Front Neurosci 10: 148. 2016. doi:10.3389/fnins.2016.00148. PMID 27092049. 
  12. ↑ 12.0 12.1 "The Case for TAAR1 as a Modulator of Central Nervous System Function". Front Pharmacol 8: 987. 2017. doi:10.3389/fphar.2017.00987. PMID 29375386. 
  13. ↑ 13.0 13.1 13.2 "Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors". Neuropharmacology 81: 283–291. June 2014. doi:10.1016/j.neuropharm.2014.02.007. PMID 24565640. 
  14. ↑ 14.0 14.1 14.2 "TAAR1 in Addiction: Looking Beyond the Tip of the Iceberg". Front Pharmacol 9: 279. 2018. doi:10.3389/fphar.2018.00279. PMID 29636691. 
  15. ↑ 15.0 15.1 15.2 15.3 "TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc". Mol Psychiatry 27 (4): 2136–2145. April 2022. doi:10.1038/s41380-022-01448-3. PMID 35079125. "Previous in vitro studies showed that TAAR1 activation stimulated several signaling cascades, including PKA, PKC, ERK1/2, and CREB [13, 38]. For example, a recent study showed that intracellular TAAR1 mediated the effects of amphetamine, a TAAR1 agonist, on RhoA and PKA signaling through G13 and to GS α-subunits on the midbrain slice of mice [39]. However, our present study showed that the TAAR1 agonist RO5166017 did not affect the activities of PKA, PKC, ERK1/2, CREB, or GSK3β, but selectively inhibited CaMKIIα in the NAc of rats. The discrepancies could be due to differences between in vitro and in vivo microenvironments. We also found that RO5166017 did not affect CaMKIIα activity in TAAR1-KO rats, indicating that the inhibitory effects of TAAR1 activation on CaMKIIα were specific.". 
  16. ↑ "Targeting Trace-Amine Associated Receptors in the Treatment of Drug Addiction". Emerging Targets for Drug Addiction Treatment. Nova Science Publishers. 2012. pp. 203–216. https://www.researchgate.net/publication/270585029. "RO5166017 lacks stimulant effects when given alone within an ample dose range (0.3-20 mg/kg). In the CPP procedure, RO5166017 did not exhibit rewarding properties within the same dose range, but failed to alter cocaine (15 mg/kg)-induced CPP (unpublished observations). These data suggest that RO5166017 does not show stimulant-like properties, displaying the capacity to prevent the hyperactivity, but not the rewarding-like effects of cocaine in the CPP paradigm." 
  17. ↑ "Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory". Int J Neuropsychopharmacol 19 (7): pyw009. July 2016. doi:10.1093/ijnp/pyw009. PMID 26822713. 
  18. ↑ "Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior". J Neurosci 37 (4): 882–892. January 2017. doi:10.1523/JNEUROSCI.2006-16.2016. PMID 28123023. 
  19. ↑ "Role of trace amine-associated receptor 1 in nicotine's behavioral and neurochemical effects". Neuropsychopharmacology 43 (12): 2435–2444. November 2018. doi:10.1038/s41386-018-0017-9. PMID 29472642. 
  20. ↑ "Robust aversive effects of trace amine-associated receptor 1 activation in mice". Neuropsychopharmacology 48 (10): 1446–1454. September 2023. doi:10.1038/s41386-023-01578-4. PMID 37055488. 
  21. ↑ "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology (Berl) 239 (10): 3345–3353. October 2022. doi:10.1007/s00213-022-06222-5. PMID 36056214. 
  22. ↑ "TAAR1 Modulates Cortical Glutamate NMDA Receptor Function". Neuropsychopharmacology 40 (9): 2217–2227. August 2015. doi:10.1038/npp.2015.65. PMID 25749299. 
  23. ↑ "Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, L-DOPA Responsivity, and Glutamatergic Neurotransmission". J Neurosci 35 (41): 14057–14069. October 2015. doi:10.1523/JNEUROSCI.1312-15.2015. PMID 26468205. 
  24. ↑ "Activation of trace amine-associated receptor 1 ameliorates PTSD-like symptoms". Biochem Pharmacol 228: 116236. October 2024. doi:10.1016/j.bcp.2024.116236. PMID 38670437. 
  25. ↑ "Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies". Chem Biol Drug Des 81 (4): 509–516. April 2013. doi:10.1111/cbdd.12018. PMID 22883051. 



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