RO5166017
 | |
| Clinical data | |
|---|---|
| Drug class | Trace amine-associated receptor 1 (TAAR1) agonist |
| Identifiers | |
| |
| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| UNII | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C12H17N3O |
| Molar mass | 219.288 g·mol−1 |
| 3D model (JSmol) | |
| |
| |
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] It is a partial agonist or near-full agonist depending on the species.[2]
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
RO5166017 is a partial agonist or near-full agonist of the TAAR1 depending on the species examined.[2] 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.[2] 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.[2] RO5166017 is selective for the TAAR1 over a large array of other targets[2]
In animal studies, RO5166017 has little effect on locomotor activity itself.[2] In contrast to psychostimulants like amphetamine and cocaine, it does not show stimulant-like or rewarding effects across a broad dose range.[3] The drug suppresses cocaine-induced hyperlocomotion and stereotypies.[2] Likewise, it suppresses hyperlocomotion induced by the NMDA receptor antagonist L-687,414.[2] In dopamine transporter (DAT) knockout mice, which show spontaneous hyperactivity in novel environments, RO5166017 suppresses hyperlocomotion.[2] These effects of RO5166017 are similar to those of antipsychotics like haloperidol and olanzapine.[2] They are absent in TAAR1 knockout mice, indicating that they are mediated by the TAAR1.[2]
RO5166017 was also shown to prevent stress-induced hyperthermia.[2] It has shown robust aversive effects in rodents as well, similarly to other TAAR1 agonists like RO5256390 and RO5263397.[4][5]
See also
References
- ^ Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC (May 2013). "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. doi:10.1038/mp.2012.57. PMID 22641180.
- ^ a b c d e f g h i j k l m Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (May 2011). "TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity". Proc Natl Acad Sci U S A. 108 (20): 8485–8490. doi:10.1073/pnas.1103029108. PMC 3101002. PMID 21525407.
- ^ Revel FG, Hoener MC, Renau-Piqueras J, Canales JJ (2012). "Targeting Trace-Amine Associated Receptors in the Treatment of Drug Addiction". In Canales JJ (ed.). Emerging Targets for Drug Addiction Treatment (PDF). Nova Science Publishers. pp. 203–216.
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.
- ^ Shabani S, Houlton S, Ghimire B, Tonello D, Reed C, Baba H, Aldrich S, Phillips TJ (September 2023). "Robust aversive effects of trace amine-associated receptor 1 activation in mice". Neuropsychopharmacology. 48 (10): 1446–1454. doi:10.1038/s41386-023-01578-4. PMC 10425385. PMID 37055488.
- ^ Liu J, Wu R, Johnson B, Zhang Y, Zhu Q, Li JX (October 2022). "Selective TAAR1 agonists induce conditioned taste aversion". Psychopharmacology (Berl). 239 (10): 3345–3353. doi:10.1007/s00213-022-06222-5. PMID 36056214.