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RO5073012
Clinical data
Other names	Ro-5073012
Drug class	Trace amine-associated receptor 1 (TAAR1) partial agonist
Identifiers
	IUPAC name 4-chloro-N-(1H-imidazol-5-ylmethyl)-N-propan-2-ylaniline;
CAS Number	1020814-70-3;
PubChem CID	24947142;
ChemSpider	28649830;
ChEMBL	ChEMBL2206375;
Chemical and physical data
Formula	C13H16ClN3
Molar mass	249.74 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC(C)N(CC1=CN=CN1)C2=CC=C(C=C2)Cl;
	InChI InChI=1S/C13H16ClN3/c1-10(2)17(8-12-7-15-9-16-12)13-5-3-11(14)4-6-13/h3-7,9-10H,8H2,1-2H3,(H,15,16); Key:AOHLEOYTKMSKPD-UHFFFAOYSA-N;

RO5073012 is a selective low-efficacy partial agonist of the trace amine-associated receptor 1 (TAAR1) which has been used in scientific research.^[1]^[2]^[3]^[4] TAAR1 partial agonists like RO5073012 can have agonist- or antagonist-like effects at the TAAR1 depending on the context and level of TAAR1 signaling.^[4]

Pharmacology

Pharmacodynamics

Actions

RO5073012 has high affinity for the mouse, rat, cynomolgus monkey, and human TAAR1 (K_i = 0.5–6 nM), is highly potent and selective as an agonist of the TAAR1 of these species (EC₅₀Tooltip half-maximal effective concentration = 8.8–25 nM), and has relatively low intrinsic activity at the TAAR1 of these species (E_maxTooltip maximal efficacy = 24–43% relative to β-phenethylamine).^[3]^[1]^[2]

RO5073012 at TAAR1 in different species^[1]^[2]
Species	Affinity (K_i, nM)	EC₅₀Tooltip half-maximal effective concentration (nM)	E_maxTooltip maximal efficacy (%)
Mouse	3.2	23	26%
Rat	1.1	25	24%
Monkey	0.5	8.8	43%
Human	5.8–6	23–25	34–35%

Effects

RO5073012 by itself has no effect on locomotor activity in normal mice.^[1] It dose-dependently suppresses cocaine-induced hyperlocomotion (a psychostimulant-like effect) in rats, with near-complete suppression of cocaine-induced locomotor stimulation at the highest dose of RO5073012.^[5]^[2] Other TAAR1 agonists, including both partial agonists and full agonists, likewise suppress psychostimulant-induced hyperlocomotion.^[6] Conversely however, and in contrast to other TAAR1 partial agonists, RO5073012 non-significantly reduced the locomotor activity induced by amphetamine in normal mice.^[3]^[5]^[1] The reasons for this difference from other TAAR1 partial agonists are unclear, though RO5073012 has notably lower TAAR1 efficacy than other TAAR1 partial agonists.^[3] RO5073012 reduces basal locomotor activity in transgenic mice with TAAR1 overexpression.^[3]^[1] Amphetamine produces only weak locomotor stimulation in mice with TAAR1 overexpression, and RO5073012, by antagonizing the TAAR1, has been found to restore dextroamphetamine-induced hyperlocomotion in this context.^[3]^[5]^[1]

Pharmacokinetics

The drug has favorable physicochemical and pharmacokinetic properties for use in vivo.^[4]^[2]^[1]

History

RO5073012 was first described in the scientific literature by 2012.^[1]^[2] It has been relatively little-studied compared to other TAAR1 partial agonists, for instance RO5166017, RO5203648, and RO5263397.^[3]

References

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ Revel FG, Meyer CA, Bradaia A, Jeanneau K, Calcagno E, André CB, Haenggi M, Miss MT, Galley G, Norcross RD, Invernizzi RW, Wettstein JG, Moreau JL, Hoener MC (November 2012). "Brain-specific overexpression of trace amine-associated receptor 1 alters monoaminergic neurotransmission and decreases sensitivity to amphetamine". Neuropsychopharmacology. 37 (12): 2580–2592. doi:10.1038/npp.2012.109. PMC 3473323. PMID 22763617.
^ ^a ^b ^c ^d ^e ^f Galley G, Stalder H, Goergler A, Hoener MC, Norcross RD (August 2012). "Optimisation of imidazole compounds as selective TAAR1 agonists: discovery of RO5073012". Bioorg Med Chem Lett. 22 (16): 5244–5248. doi:10.1016/j.bmcl.2012.06.060. PMID 22795332.
^ ^a ^b ^c ^d ^e ^f ^g 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. Among all the TAAR1 agonists, RO5073012 is the least well-characterized, as only one study has examined its pharmacological properties [44]. Consistent with other selective TAAR1 agonists, RO5073012 has high affinity at TAAR1 from different species when expressed ex vivo. It exhibits high potency and selectivity at TAAR1 but has low intrinsic efficacy (maximal cAMP level reached 24–43%), showing a partial agonist profile[44]. However, since it was suggested that partial agonists can act as an antagonist depending on endogenous intrinsic activity of the receptor, it was used to reduce the activity of TAAR1 in TAAR1-OE mice. RO5073012 significantly restored sensitivity to amphetamine in TAAR1-OE mice with amphetamine-induced hypolocomotion, and had no effect on locomotion in the control group [44]. Interestingly, it did not prevent amphetamine-induced increase in locomotor activity in WT mice [44], which is contrary to other TAAR1 partial agonists. However, since we have very limited knowledge of the in vivo pharmacological effects of RO5073012, additional studies are needed to further examine why RO5073012 failed to prevent amphetamine-induced increase in locomotor activity in WT mice while other TAAR1 partial agonists did, as well as to further evaluate its potential in modulating drug abuse-related behaviors.
^ ^a ^b ^c Lam VM, Espinoza S, Gerasimov AS, Gainetdinov RR, Salahpour A (September 2015). "In-vivo pharmacology of Trace-Amine Associated Receptor 1". Eur J Pharmacol. 763 (Pt B): 136–142. doi:10.1016/j.ejphar.2015.06.026. PMID 26093041. Based on the full agonist pharmacophore RO5166017, three new analogs were developed that displayed partial agonism on TAAR1 (Galley et al., 2012; Revel et al., 2012a, 2012b, 2012c). These three new partial agonist (RO5263397, RO5203648, and RO5073012) are highly selective for TAAR1 and have similar favorable pharmacokinetic profiles as the full agonist. One of the interesting properties of partial agonists is that they can act as an agonist or antagonist based on endogenous intrinsic activity of the receptor or the amount of neurotransmitter levels available in the surrounding environment. Interestingly, both RO5263397 and RO52603648 augment the firing rate of dopaminergic neurons similar to what was observed with the antagonist EPPTB. However, in vivo behavioral tests showed the partial agonists to act in a similar fashion to TAAR1 full agonists. For instance, it was found that RO5263397, RO5203648, and RO5073012 reduced hyperlocomotion induced by psychostimulant administration (Revel et al., 2012a, 2012b, 2012c).
^ ^a ^b ^c Jing L, Li JX (August 2015). "Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction". Eur J Pharmacol. 761: 345–352. doi:10.1016/j.ejphar.2015.06.019. PMC 4532615. PMID 26092759.
^ Dedic N, Dworak H, Zeni C, Rutigliano G, Howes OD (December 2021). "Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies". Int J Mol Sci. 22 (24): 13185. doi:10.3390/ijms222413185. PMC 8704992. PMID 34947997.