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| Other names | C22 |
| Drug class | Trace amine-associated receptor 1 (TAAR1)antagonist; Other unknown actions |
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| Chemical and physical data | |
| Formula | C17H16Cl2N4 |
| Molar mass | 347.24 g·mol−1 |
| 3D model (JSmol) | |
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Compound 22 is a low-potency andnon-selectivetrace amine-associated receptor 1 (TAAR1)antagonist that was identified in 2015 and was further studied in animals in 2018.[1][2] The drug enhances thefiring rates ofdopaminergicneuronsex vivo and potentiatespsychostimulant-inducedhyperlocomotion andstereotypy in rodentsin vivo.[2] The latter effects are partially or fully independent of the TAAR1 however, with themechanisms underlying these effects being unknown.[2] Compound 22, along withEPPTB andRTI-7470-44, is one of the only TAAR1 antagonists that has been identified as of 2022.[2][3]
Compound 22 is a low-potencyantagonist of thetrace amine-associated receptor 1 (TAAR1).[2] It has shown significant inhibition of TAAR1signaling at a concentration of 100 μMin vitro.[2] The drug'sIC50Tooltip half-maximal inhibitory concentration value for TAAR1 antagonism is unknown but is greater than 100 μM.[2]
Compound 22 was also screened foroff-target activity at 47 targets at a concentration of 10 μM.[2] The screened targets includedmonoamine receptors,monoamine transporters,histamine receptors,muscarinic acetylcholine receptors,glutamate receptors,GABA receptors,opioid receptors, andsigma receptors.[2] There were five hits (>50% binding inhibition), which included theserotonin transporter (SERT),dopamine transporter (DAT), andnorepinephrine transporter (NET), as well as thesigmaσ1 andσ2 receptors.[2] Itsaffinities (Ki) were 1,800 nM for the SERT, 1,053 nM for the DAT, 1,902 nM for the NET, 276 nM for the sigma σ1 receptor, and 412 nM for the sigma σ2 receptor.[2] Although compound 22 bound with significant affinity to the DAT, it did notinhibit dopamine reuptake and did not interfere withcocaine-induced dopamine reuptake inhibition at concentrations of up to 100 μM.[2]
Compound 22 increases thefiring rate ofdopaminergicneurons in mouseventral tegmental area (VTA)slicesex vivo similarly to the TAAR1 antagonistEPPTB.[2] It increased the firing rate by 88% at a concentration of 100 μM, whereas EPPTB increased the firing rate by 74% at a concentration of 10 nM.[2]
Compound 22 decreased basallocomotor activity in micein vivo significantly by 58% at 5 mg/kg and non-significantly by 26% at 30 mg/kg.[2] It was not found to stimulate locomotion at any dose.[2] In subsequent experiments, compound 22 did not significantly affect locomotor activity at 5 or 25 mg/kg in either normal mice or TAAR1knockout mice.[2]
The drugdose-dependently enhancedamphetamine-inducedhyperlocomotion in mice.[2] The increases were 28% at 5 mg/kg, 44% at 15 mg/kg, 57% at 20 mg/kg, and 77% at 30 mg/kg, but no difference at 50 mg/kg.[2] Compound 22 likewise potentiatedcocaine-induced hyperlocomotion in mice.[2] The increases were 77% at 5 mg/kg, 84% at 15 mg/kg, and 124% at 25 mg/kg.[2] Compound 22 augmented amphetamine- and cocaine-inducedstereotypy as well.[2]
In subsequent experiments, compound 22 potentiated amphetamine-induced hyperlocomotion in normal mice by 44% at a dose of 5 mg/kg but had no significant effect at doses of 2.5 and 15 mg/kg.[2] In TAAR1 knockout mice, compound 22 augmented amphetamine-induced hyperlocomotion by 84% at a dose of 15 mg/kg.[2] The drug dose-dependently potentiated cocaine-induced hyperlocomotion at doses of 5, 15, and 25 mg/kg to similar extents in both normal mice and TAAR1 knockout mice.[2] Similar effects of compound 22 were found for amphetamine- and cocaine-induced stereotypy in normal mice and TAAR1 knockout mice.[2]
On the basis of the preceding findings, it was concluded that compound 22 augmentspsychostimulant-induced hyperlocomotion in a manner that is partially or fully independent of TAAR1 antagonism.[2] Thebiological targets andmechanisms of compound 22 mediating these effects are unknown.[2]
Compound 22 was predicted to have goodphysicochemical andpharmacokinetic properties and to be able to cross theblood–brain barrier.[2] As an example, its predictedlogP is 3.3 to 3.7.[2][4] In accordance with predictions, compound showed clearcentrally mediated effects in rodents, indicating that it indeed crosses the blood–brain barrier.[2]
Compound 22 was identified in 2015 byvirtual screening of over 3 million compounds at the human TAAR1in silico followed by experimental evaluation of 42 top candidate compounds at the TAAR1in vitro.[1][2] Compound 22 is one of the only TAAR1 antagonists that has been identified as of 2022.[3]