Preladenant is a high selective antagonist of adenosine A2A receptor with Ki value of 1.1 nM [1].
Parkinson's Disease is characterized by the loss of dopaminergic neuronal projection. The patients with PD lost the capability to control their muscles. As an antagonist of adenosine A2A receptor, preladenant is a non-dopaminergic drug developed for the treatment of PD. This compound showed potency in Phase II clinical trials but failed in Phase III trials and so was discontinued. Preladenant is a methoxyethoxy derivative of the previously discovered A2A receptor antagonist SCH 58261 and has much higher selectivity for A2A receptors over A1 receptors [1 and 2].
Preladenant was obtained through modifying the phenethyl side chain of SCH 58261. It exerted higher binding affinity for both rat and human A2A receptors with Ki values of 2.5 and 1.1 nM, respectively. Preladenant also showed more than 1000-fold higher selectivity for A2A receptors over other adenosine receptors. The Ki values of preladenant for A1, A3 and A2B receptors are all above 1000 nM. Besides that, preladenant showed no significant affinity for a panel of 59 other enzymes, receptors and ion channels. In the cell assays, preladenant also inhibited the activity of both human and rat adenylate cyclase stimulated by CGS 21680 (an agonist of A2A receptor) with Kb values of 1.3 and 0.7 nM, respectively [1].
Preladenant also showed efficacies in animal models. In cynomolgus monkeys treated with MPTP, administration of preladenant at dose of both 1 and 3 mg/kg resulted in parkinsonian scores reduction. In a Dunnets post hoc test, the combination treatment of preladenant and L-Dopa significantly increased the locomotor activity by 80%. Besides that, preladenant was found to have anti- catalepsy effects and dose of 0.3 mg/kg and significantly reduce the hypolocomotion caused by CGS-21680 at dose of 0.1 mg/kg in rats models [2 and 3].
参考文献:
[1] Neustadt B R, Hao J, Lindo N, et al. Potent, selective, and orally active adenosine A 2A receptor antagonists: arylpiperazine derivatives of pyrazolo [4, 3-e]-1, 2, 4-triazolo [1, 5-c] pyrimidines. Bioorganic & medicinal chemistry letters, 2007, 17(5): 1376-1380.
[2] Hodgson R A, Bedard P J, Varty G B, et al. Preladenant, a selective A 2A receptor antagonist, is active in primate models of movement disorders. Experimental neurology, 2010, 225(2): 384-390.
[3] Hodgson R A, Bertorelli R, Varty G B, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2, 4-difluorophenyl]-1-piperazinyl] ethyl]-2-(2-furanyl)-7H-pyrazolo [4, 3-e][1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine] in rodent models of movement disorders and depression. Journal of Pharmacology and Experimental Therapeutics, 2009, 330(1): 294-303.
| Cell experiment: [1] | |
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Cell lines |
Primary actin-GFP microglia |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months. |
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Reaction Conditions |
1 μM, 15 min |
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Applications |
Three-dimensional cell reconstructions from primary actin-GFP microglia grown in Matrigel were used to determine cell ramification (expressed as surface area-to-volume ratios) in response to preladenant treatment. Preladenant at concentration of 1 μM prevented the adenosine-induced process retraction in activated microglia. |
| Animal experiment : [2] | |
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Animal models |
Male CD rats |
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Dosage form |
Haloperidol (1 mg/kg s.c.) was administered to induce catalepsy in the rats. Preladenant was administered orally after the 30-min baseline measure, and catalepsy was retested 1 and 4 h after administration. |
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Applications |
Preladenant dose-dependently attenuated the cataleptic effects of haloperidol 1h [F(3,20) = 5.0, p < 0.01] and 4 h [F(3,20) = 9.8, p < 0.01] after dosing, with statistically significant effects at doses of 0.3 and 1 mg/kg at both time points. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: [1] Gyoneva S, Davalos D, Biswas D, et al. Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia, 2014. [2] Hodgson R A, Bertorelli R, Varty G B, et al. Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2, 4-difluorophenyl]-1-piperazinyl] ethyl]-2-(2-furanyl)-7H-pyrazolo [4, 3-e][1, 2, 4] triazolo [1, 5-c] pyrimidin-5-amine] in rodent models of movement disorders and depression. Journal of Pharmacology and Experimental Therapeutics, 2009, 330(1): 294-303. | |
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