-VU0155041 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C14H15CL2NO3 |
| Molecular Weight | 316.179802179337 |
| Exact Mass | 315.042 |
| CAS # | 1263273-14-8 |
| Related CAS # | VU0155041;1093757-42-6;VU0155041 sodium;1259372-69-4 |
| PubChem CID | 888023 |
| Appearance | White to off-white solid powder |
| LogP | 3.4 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 3 |
| Heavy Atom Count | 20 |
| Complexity | 367 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | O=C([C@H]1[C@@H](C(NC2=CC(Cl)=CC(Cl)=C2)=O)CCCC1)O |
| InChi Key | VSMUYYFJVFSVCA-NWDGAFQWSA-N |
| InChi Code | InChI=1S/C14H15Cl2NO3/c15-8-5-9(16)7-10(6-8)17-13(18)11-3-1-2-4-12(11)14(19)20/h5-7,11-12H,1-4H2,(H,17,18)(H,19,20)/t11-,12+/m0/s1 |
| Chemical Name | (1R,2S)-2-[(3,5-dichlorophenyl)carbamoyl]cyclohexane-1-carboxylic acid |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Metabotropic glutamate receptor 4 (mGluR4) (Positive allosteric modulator with partial agonist activity). The compound exhibits selectivity for mGluR4 over other mGluR subtypes (mGluR1, 2, 5, 7, 8) and did not show significant activity at 67 other off-target GPCRs, ion channels, and transporters. It also did not antagonize NMDA receptor functional activity. [1] |
| ln Vitro |
The efficacy of the cis regioisomer of VU0155041 was similar in human and rat receptors (798±58 nM for human mGluR4 and 693±140 nM for rat mGluR4). In contrast, the concentration response curve for the trans regioisomer (VU0155040) did not approach a plateau at the maximum measured concentration. Fold-shift tests with 30 μM VU0155041 also demonstrated that the cis regioisomer at this dose was more effective against both human and rat mGluR4. VU0155041 induced a concentration-dependent shift in the baseline when investigated experimentally using thallium flux tests for fold shifts. VU0155041 generated a response that reached approximately 45% of the maximal glutamate response. VU0155041 is a partial agonist of mGluR4 and activates the receptor by engaging with a region different from the glutamate binding site. VU0155041 exhibits selectivity for mGluR4 against 67 other targets and does not influence the function of striatal NMDA receptors [1]. VU0155041, the cis-regioisomer of the lead compound VU0003423, was a potent and selective positive allosteric modulator (PAM) of human and rat mGluR4. At human mGluR4, its potency (EC50) for potentiating an EC20 glutamate response was 798 ± 58 nM. At rat mGluR4, the potency was 693 ± 140 nM. In fold-shift experiments, a 30 µM concentration of VU0155041 caused a 6.4 ± 0.7-fold leftward shift in the glutamate concentration-response curve at human mGluR4 and a 4.7 ± 0.4-fold shift at rat mGluR4. Furthermore, VU0155041 exhibited partial allosteric agonist activity at rat mGluR4, reaching approximately 45% of the maximal glutamate response with an EC50 of 2.5 ± 0.5 µM. This agonist activity was not blocked by the orthosteric antagonist LY341495. VU0155041 did not potentiate or antagonize responses at mGluR1, 2, 5, 7, or 8 at 30 µM. It also had no effect on NMDA receptor-mediated currents in striatal medium spiny neurons at 10 µM. [1] |
| ln Vivo |
VU0155041: Soluble in aqueous solutions, rats' haloperidol- and reserpine-induced akinesia is dose-dependently decreased by intracerebroventricular injection of 31 to 316 nM VU0155041. The tetanic effects of haloperidol were likewise considerably lessened by VU0155041 at dosages of 31 and 92 nmol, and the compound's effects lasted for 30 minutes after infusion. Akinesia was similarly markedly improved by intravenous infusion of VU0155041 at a dose of 316 nmol [1]. Intracerebroventricular (icv) administration of VU0155041 produced antiparkinsonian effects in two rodent models. In haloperidol-induced catalepsy in rats, icv infusion of 31 and 93 nmol of VU0155041 significantly decreased catalepsy scores at 15 and 30 minutes post-injection. In the reserpine-induced akinesia model in rats, icv infusion of a 316 nmol dose of VU0155041 resulted in a significant reversal of akinesia, measured as an increase in locomotor activity. [1] |
| Enzyme Assay |
A GTPγS binding assay was used to assess activity at human mGluR2. Membranes were homogenized in ice-cold binding buffer. Assay mixtures contained membrane protein, test compound, glutamate, [³⁵S]GTPγS, and GDP. After incubation at room temperature with shaking, the reaction was terminated by rapid filtration through filter plates, which were then washed, dried, and counted for radioactivity. Nonspecific binding was determined in the presence of excess unlabeled GTPγS. [1] |
| Cell Assay |
Two primary cell-based assays were used. For the calcium mobilization assay, human mGluR4 cells stably transfected with a chimeric Gq protein were plated in 384-well plates. Cells were loaded with a fluorescent calcium indicator dye. After dye removal and addition of assay buffer, test compounds were added, followed by EC20 and EC80 concentrations of glutamate. Calcium flux was measured using a kinetic imaging plate reader. For the thallium flux assay, rat mGluR4 cells co-expressed with GIRK potassium channels were used. Cells were plated and loaded with a thallium-sensitive fluorescent dye. After dye removal, test compounds were added, followed by an EC20 or EC80 concentration of agonist (glutamate or L-AP4). Thallium flux was measured using the same imaging system. Potency and fold-shift experiments were conducted using these assays. [1] |
| Animal Protocol |
For the haloperidol-induced catalepsy model, male Sprague-Dawley rats with third ventricle cannulas were used. Catalepsy was induced by intraperitoneal injection of haloperidol (1.5 mg/kg). Two hours later, cataleptic rats received icv infusions of vehicle, L-AP4 (100-1000 nmol), or VU0155041 (31 or 93 nmol). Catalepsy was measured by placing the rat's forepaws on a horizontal bar and recording the latency to remove them, assessed at 15, 30, and 60 minutes post-infusion. For the reserpine-induced akinesia model, rats were injected subcutaneously with reserpine (5 mg/kg). Two hours later, baseline locomotor activity was measured for 30 minutes in photobeam activity cages. Rats then received a single icv injection of vehicle, L-AP4 (100, 300, or 1000 nmol), or VU0155041 (93 or 316 nmol), and motor activity was recorded for an additional 30 minutes. VU0155041 was dissolved in 1 N sodium hydroxide, diluted with water, pH adjusted to 7.4 with HCl, and brought to final volume with water. [1] |
| ADME/Pharmacokinetics |
The aqueous solubility of VU0155041 was noted as an improvement over the previous PAM PHCCC, allowing formulation in an aqueous vehicle for icv administration. No other ADME/PK parameters (e.g., absorption, distribution, metabolism, excretion, half-life, oral bioavailability) were reported in this study. [1] |
| References |
[1]. Discovery, characterization, and antiparkinsonian effect of novel positiveallosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol. 2008 Nov;74(5):1345-58. |
| Additional Infomation |
VU0155041 was discovered via high-throughput screening as a novel mGluR4 PAM based on a cyclohexyl amide scaffold, distinct from the previously known PAM PHCCC. It acts as a mixed allosteric agonist/PAM, activating mGluR4 at a site distinct from the orthosteric (glutamate) binding site. Its mechanism for antiparkinsonian effect is proposed to involve modulation of the overactive indirect pathway in the basal ganglia by reducing GABA release at the striatopallidal synapse. The improvements in potency, selectivity, and aqueous solubility over PHCCC make VU0155041 a valuable tool compound for exploring mGluR4's role in physiology and its potential as a therapeutic target for Parkinson's disease. [1] |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~158.14 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.1628 mL | 15.8138 mL | 31.6276 mL | |
| 5 mM | 0.6326 mL | 3.1628 mL | 6.3255 mL | |
| 10 mM | 0.3163 mL | 1.5814 mL | 3.1628 mL |