VU0152100

• CAT Number: I003489
• CAS Number: 409351-28-6
• Molecular Formula: C18H19N3O2S
• Molecular Weight: 341.43
• Purity: ≥95%
• Target: AChR
• Solubility: DMSO >50 mg/mL
• Storage: Store at -20C
• IC50: 380 ± 93 nM (EC50) [1]

VU0152100 is a potent and selective allosteric potentiator of M4 mAChR with an EC50 of 380 ± 93 nM.IC50 Value: 380 ± 93 nM (EC50) [1]Target: M4 mAChRin vitro: VU0152100 was selective for M4 relative to M1, M2, M3, and M5. VU0152100 dose-dependently potentiated the response to an EC20 concentration of ACh with EC50 values of 1.9 ± 0.2 M, and increased the maximal response to ACh to approximately 130%. VU0152100 (10 M) also enhanced the potency of ACh to induce GIRK-mediated thallium flux, as manifest by a robust (≈30-fold) leftward shift in the ACh CRC from 77 ± 1.2 nM (veh) to 2.35 ± 0.5 nM (VU0152100) [1].in vivo: Systemic administration of VU0152099 and VU0152100 provides robust brain levels of these compounds, the effects of VU0152099 and VU0152100 were evaluated in reversing amphetamine-induced hyperlocomotion in rats using a dose of 56.6 mg/kg i.p. for each compound with a 30-min pretreatment interval [1].

Reference

1:Neuropsychopharmacology. 2014 Jun;39(7):1578-93. doi: 10.1038/npp.2014.2. Epub 2014 Jan 20. Antipsychotic drug-like effects of the selective M4 muscarinic acetylcholine receptor positive allosteric modulator VU0152100.Byun NE,Grannan M,Bubser M,Barry RL,Thompson A,Rosanelli J,Gowrishankar R,Kelm ND,Damon S,Bridges TM,Melancon BJ,Tarr JC,Brogan JT,Avison MJ,Deutch AY,Wess J,Wood MR,Lindsley CW,Gore JC,Conn PJ,Jones CK, PMID: 24442096 PMCID: PMC4023154 DOI: 10.1038/npp.2014.2 Abstract: Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.