The drug is important for the study of the TAAR1 receptor, as while numerous other compounds are known which act as TAAR1 agonists, such asmethamphetamine,MDMA, and3-iodothyronamine, all previously known TAAR1 agonists are either weak and rapidlymetabolized (endogenousligands), 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.
RO5166017 is apartial agonist or near-full agonist of the TAAR1 depending on thespecies examined.[4][3] ItsEC50Tooltip half-maximal effective concentration values are 3.3 to 8.0nM for the mouse TAAR1 (mTAAR1), 14nM for the rat TAAR1 (rTAAR1), 97nM for thecynomolgus monkey TAAR1, and 55nM for the human TAAR1.[4][3] ItsEmaxTooltip maximal efficacy 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 isselective for the TAAR1 over a large array of othertargets.[3]
Previousin-vitro studies found that TAAR1 could activate severalsignaling cascades includingPKA,PKC,ERK1/2, andCREB.[15] However, RO5166017 did not affect these signaling pathways, norGSK3β, in ratsin vivo, and instead selectively and TAAR1-dependently inhibitedCaMKIIα activity in the NAc.[15]
RO5166017 has been found to inhibit expression, though not reconsolidation or retention, of cocaine-inducedconditioned 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-inducedrelapse-like behaviors in rodents as well.[1][18][15] As with cocaine, RO5166017 has been found to inhibitnicotine-induced dopamine release in the NAc and to reduce nicotine intake and relapse-like behaviors.[1][5][19]
^abcdLiu J, Wu R, Seaman R, Manz KM, Johnson B, Vu J, Huang Y, Zhang Y, Robison AJ, Neve R, Grueter BA, Dietz D, Li JX (April 2022)."TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc".Mol Psychiatry.27 (4):2136–2145.doi:10.1038/s41380-022-01448-3.PMC9829124.PMID35079125.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.
^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. 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.
^Peng L, Zhang J, Feng J, Ge J, Zou Y, Chen Y, Xu L, Zeng Y, Li JX, Liu J (October 2024). "Activation of trace amine-associated receptor 1 ameliorates PTSD-like symptoms".Biochem Pharmacol.228 116236.doi:10.1016/j.bcp.2024.116236.PMID38670437.
^Cichero E, Espinoza S, Gainetdinov RR, Brasili L, Fossa P (April 2013). "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.doi:10.1111/cbdd.12018.hdl:11380/1061774.PMID22883051.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
