(1R,2S)-VU0155041 - CAS 1263273-14-8
Category: Inhibitor
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Molecular Formula:
Molecular Weight:
(1R,2S)-VU0155041 is a partial mGluR4-positive allosteric modulator (EC50= 2.35 μM) that dependently attenuated hyperalgesia in neuropathic pain model rats.
Brife Description:
A partial mGluR4 agonist (EC50= 2.35 μM)
(1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acid; VU 0155041; VU-0155041; VU0155041
DMSO: ≥ 59 mg/mL
Store in a cool and dry place (or refer to the Certificate of Analysis).
Boiling Point:
540.2±50.0 ℃ at 760 Torr
1.429±0.06 g/cm3
Canonical SMILES:
1.Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4.
Niswender CM;Johnson KA;Weaver CD;Jones CK;Xiang Z;Luo Q;Rodriguez AL;Marlo JE;de Paulis T;Thompson AD;Days EL;Nalywajko T;Austin CA;Williams MB;Ayala JE;Williams R;Lindsley CW;Conn PJ Mol Pharmacol. 2008 Nov;74(5):1345-58. doi: 10.1124/mol.108.049551. Epub 2008 Jul 29.
Parkinson's disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia and results in antiparkinsonian effects in rodent PD models. N-Phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC) is a positive allosteric modulator (PAM) of mGluR4 that has been used to further validate the role of mGluR4 in PD, but the compound suffers from a lack of selectivity, relatively low potency, and poor solubility. Via high-throughput screening, we discovered more than 400 novel PAMs of mGluR4. Compounds derived from a novel chemical scaffold were characterized in vitro at both rat and human mGluR4 using two distinct assays of mGluR4 function. The lead compound was approximately 8-fold more potent than PHCCC, enhanced the potency of glutamate at mGluR4 by 8-fold, and did not show any significant potentiator or antagonist activity at other mGluR subtypes. Resolution of the regioisomers of the lead revealed that the cis regioisomer, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), contained the majority of the mGluR4 PAM activity and also exhibited partial agonist activity at mGluR4 at a site that was distinct from the glutamate binding site, suggesting that this compound is a mixed allosteric agonist/PAM of mGluR4.
2.Allosteric modulation of the group III mGlu4 receptor provides functional neuroprotection in the 6-hydroxydopamine rat model of Parkinson's disease.
Betts MJ;O'Neill MJ;Duty S Br J Pharmacol. 2012 Aug;166(8):2317-30. doi: 10.1111/j.1476-5381.2012.01943.x.
BACKGROUND AND PURPOSE: ;We recently reported that broad spectrum agonist-induced activation of presynaptic group III metabotropic glutamate (mGlu) receptors within the substantia nigra pars compacta using L-2-amino-4-phosphonobutyrate provided functional neuroprotection in the 6-hydroxydopamine lesion rat model of Parkinson's disease. The aim of this study was to establish whether selective activation of the mGlu(4) receptor alone could afford similar functional neuroprotection.;EXPERIMENTAL APPROACH: ;The neuroprotective effects of 8 days of supranigral treatment with a positive allosteric modulator of mGlu(4) receptors, (+/-)-cis-2-(3,5-dichlorphenylcarbamoyl)cyclohexanecarboxylic acid (VU0155041), were investigated in rats with unilateral 6-hydroxydopamine lesions. The effects of VU0155041 treatment on motor function were assessed using both habitual (cylinder test) and forced (adjusted stepping, amphetamine-induced rotations) behavioural tests. Nigrostriatal tract integrity was examined by analysis of tyrosine hydroxylase, dopa decarboxylase or dopamine levels in the striatum and tyrosine hydroxylase-positive cell counts in the substantia nigra pars compacta.;KEY RESULTS: ;VU0155041 provided around 40% histological protection against a unilateral 6-hydroxydopamine lesion as well as significant preservation of motor function.
3.Dorsal striatum metabotropic glutamate receptor 8 affects nocifensive responses and rostral ventromedial medulla cell activity in neuropathic pain conditions.
Rossi F;Marabese I;De Chiaro M;Boccella S;Luongo L;Guida F;De Gregorio D;Giordano C;de Novellis V;Palazzo E;Maione S J Neurophysiol. 2014 Jun 1;111(11):2196-209. doi: 10.1152/jn.00212.2013. Epub 2013 Dec 4.
The present study investigated the role of metabotropic glutamate receptor subtype 8 (mGluR8) in the dorsal striatum (DS) in modulating thermonociception and rostral ventromedial medulla (RVM) ON and OFF cell activities in conditions of neuropathic pain induced by spared nerve injury (SNI) of the sciatic nerve in rats. The role of DS mGluR8 on mechanical allodynia was also investigated. Intra-DS (S)-3,4-dicarboxyphenylglycine [(S)-3,4-DCPG], a selective mGluR8 agonist, did not modify the activity of the ON and OFF cells in sham-operated rats. In SNI rats, which showed a reduction of the mechanical withdrawal threshold, intra-DS microinjection of (S)-3,4-DCPG inhibited the ongoing and tail flick-evoked activity of the ON cells while increasing the activity of the OFF cells. AZ12216052, a selective mGluR8 positive allosteric modulator (PAM), behaved like (S)-3,4-DCPG in increasing tail flick latency and OFF cell activity and decreasing ON cell activity in SNI rats only but was less potent. VU0155041, a selective mGluR4 PAM, was ineffective in changing thermal nociception and ON and OFF cell activity in both sham-operated and SNI rats. (S)-3,4-DCPG did not change mechanical withdrawal threshold in sham-operated rats but increased it in SNI rats.
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CAS 1263273-14-8 (1R,2S)-VU0155041

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