Compound 22 (TAAR1 antagonist)
Compound 22 is a low-potency and non-selective trace amine-associated receptor 1 antagonist that was identified in 2015 and was further studied in animals in 2018. The drug enhances the firing rates of dopaminergic neurons ex vivo and potentiates psychostimulant-induced hyperlocomotion and stereotypy in rodents in vivo. The latter effects are partially or fully independent of the TAAR1 however, with the mechanisms underlying these effects being unknown. Compound 22, along with EPPTB and RTI-7470-44, is one of the only TAAR1 antagonists that has been identified as of 2022.
Pharmacology
Pharmacodynamics
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Compound 22 is a low-potency antagonist of the trace amine-associated receptor 1. It has shown significant inhibition of TAAR1 signaling at a concentration of 100μM in vitro. The drug's value for TAAR1 antagonism is unknown but is greater than 100μM.Compound 22 was also screened for off-target activity at 47targets at a concentration of 10μM. The screened targets included monoamine receptors, monoamine transporters, histamine receptors, muscarinic acetylcholine receptors, glutamate receptors, GABA receptors, opioid receptors, and sigma receptors. There were five hits, which included the serotonin transporter, dopamine transporter, and norepinephrine transporter, as well as the sigma σ1 and σ2 receptors. Its affinities were 1,800nM for the SERT, 1,053nM for the DAT, 1,902nM for the NET, 276nM for the sigma σ1 receptor, and 412nM for the sigma σ2 receptor. Although compound 22 bound with significant affinity to the DAT, it did not inhibit dopamine reuptake and did not interfere with cocaine-induced dopamine reuptake inhibition at concentrations of up to 100μM.
Effects
Compound 22 increases the firing rate of dopaminergic neurons in mouse ventral tegmental area slices ex vivo similarly to the TAAR1 antagonist EPPTB. It increased the firing rate by 88% at a concentration of 100μM, whereas EPPTB increased the firing rate by 74% at a concentration of 10nM.Compound 22 decreased basal locomotor activity in mice in vivo significantly by 58% at 5mg/kg and non-significantly by 26% at 30mg/kg. It was not found to stimulate locomotion at any dose. In subsequent experiments, compound 22 did not significantly affect locomotor activity at 5 or 25mg/kg in either normal mice or TAAR1 knockout mice.
The drug dose-dependently enhanced amphetamine-induced hyperlocomotion in mice. The increases were 28% at 5mg/kg, 44% at 15mg/kg, 57% at 20mg/kg, and 77% at 30mg/kg, but no difference at 50mg/kg. Compound 22 likewise potentiated cocaine-induced hyperlocomotion in mice. The increases were 77% at 5mg/kg, 84% at 15mg/kg, and 124% at 25mg/kg. Compound 22 augmented amphetamine- and cocaine-induced stereotypy as well.
In subsequent experiments, compound 22 potentiated amphetamine-induced hyperlocomotion in normal mice by 44% at a dose of 5mg/kg but had no significant effect at doses of 2.5 and 15mg/kg. In TAAR1 knockout mice, compound 22 augmented amphetamine-induced hyperlocomotion by 84% at a dose of 15mg/kg. The drug dose-dependently potentiated cocaine-induced hyperlocomotion at doses of 5, 15, and 25mg/kg to similar extents in both normal mice and TAAR1 knockout mice. Similar effects of compound 22 were found for amphetamine- and cocaine-induced stereotypy in normal mice and TAAR1 knockout mice.
On the basis of the preceding findings, it was concluded that compound 22 augments psychostimulant-induced hyperlocomotion in a manner that is partially or fully independent of TAAR1 antagonism. The biological targets and mechanisms of compound 22 mediating these effects are unknown.