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Research ArticleNeuropharmacology

MLi-2, a Potent, Selective, and Centrally Active Compound for Exploring the Therapeutic Potential and Safety of LRRK2 Kinase Inhibition

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587
Matthew J. Fell
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Christian Mirescu
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Kallol Basu
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Boonlert Cheewatrakoolpong
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Duane E. DeMong
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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J. Michael Ellis
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Lynn A. Hyde
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Yinghui Lin
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Carrie G. Markgraf
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Hong Mei
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Michael Miller
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Frederique M. Poulet
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Jack D. Scott
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Michelle D. Smith
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Zhizhang Yin
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Xiaoping Zhou
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Eric M. Parker
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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Matthew E. Kennedy
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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John A. Morrow
Neuroscience Discovery (M.J.F., C.M., M.E.K) and Discovery Chemistry (J.M.E), Merck Research Laboratories, Boston, Massachusetts; Discovery Chemistry (K.B., D.E.D., M.M., J.D.S.), Pharmacology (B.C., L.A.H., Y.L., E.M.P., M.D.S., Z.Y., X.Z.), Pathology and Cellular Toxicology (C.G.M., F.M.P), and Pharmacokinetics (H.M.), Merck Research Laboratories, Kenilworth, New Jersey; Neuroscience Discovery, Merck Research Laboratories, West Point, Pennsylvania (J.A.M.)
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  • Fig. 1.
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    Fig. 1.

    Structure and enzymatic activity of MLi-2. (A) Chemical Structure of cis-2,6-dimethyl-4-(6-(5-(1-methylcyclopropoxy)-1H-indazol-3-yl)pyrimidin-4-yl)morpholine (MLi-2). (B) GST-LRRK2 [G2019S] (1326–2527) was assayed using 400 nM LRRKtide in the presence of 134 μM ATP with the indicated concentrations of MLi-2. The results are presented as percentage inhibition of kinase activity. Results are averages of quadruplicate reactions. (C) Western blot and (D) quantification of the MLi-2 dose response for inhibition of pSer935 LRRK2 in Tet-inducible LRRK2 SHSY5Y cells. The results are presented as mean percent inhibition by MLi-2, calculated as the change from dimethylsulfoxide (DMSO) control samples.

  • Fig. 2.
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    Fig. 2.

    Whole-cell LRRK2 radioligand binding. (A) Chemical structure of LRRK2 radioligand ([35S]MLi-A). (B) Whole-cell saturation binding with increasing concentrations of [35S]MLi-A in Tet-inducible wild-type LRRK2 expressing SHSY5Y cells. Binding was performed in the absence of induction (noninduced) or where expression was induced for 48 hours in the presence of tetracycline (Tet-induced). The results are presented as specific binding and are averages of triplicate reactions. The KD value, in nM, is derived from the graph. (C) Displacement of [35S]MLi-A binding with MLi-2. Experiments were performed with 0.7 nM [35S]MLi-A and increasing concentrations of MLi-2. The results are presented as specific binding and are averages of triplicate reactions. The Ki value, in nM, is derived from the graph. CPM, counts per minute.

  • Fig. 3.
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    Fig. 3.

    Effect of oral administration of various doses of MLi-2 on pSer935 LRRK2 in the brains of mice after acute, single administration. (A) Western blot and (B) quantification of LRRK2 pSer935 LRRK2 levels. (C) Unbound brain concentration of MLi-2. Data are mean ± S.E.M.; n = 5 mice per treatment group.*P < 0.05–P < 0.001 compared with the vehicle-treated animals.

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    Fig. 4.

    Effect of MLi-2 (3–120 mg/kg per day) on pSer935 LRRK2 (ratio of pSer935/total LRRK2) and total LRRK2 (total LRRK2/GAPDH) in the brains of mice after 11 days of in-diet dosing. (A) Western blot showing pSer935 LRRK2 and total LRRK2. (B) and (C) shows the quantification of pSer935 LRRK2 and total LRRK2, respectively. (D) Unbound brain concentrations of MLi-2 on day 11 in mice administered MLi-2 in diet for 11 days. Open circles, 3 mg/kg per day; 10 mg/kg per day, open squares; 30 mg/kg per day, closed triangles; 60 mg/kg per day, open triangles; and 100 mg/kg, closed circles. (E) pSer935 LRRK2 levels (ratio of pSer935/total LRRK2 expressed as a percentage of the vehicle control group) in the brains of mice versus unbound brain concentrations of MLi-2 (3–120 mg/kg per day) on day 11 of in-diet dosing. Mice were euthanized a 4, 8, and 24 hours after the start of the dark cycle on day 11 of dosing. Data are mean ± S.E.M.; n = 5 per treatment group; ***P < 0.001 compared with the vehicle diet–treated animals.

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    Fig. 5.

    Chronic in-diet dosing with MLi-2 (30 mg/kg per day) is well tolerated and leads to sustained inhibition of CNS LRRK2 kinase activity. (A) Bodyweight, (B) food intake, and (C) dose achieved per week of the study. Effect of MLi-2 at 30 mg/kg per day on pSer935 LRRK2 levels in the cortex of mice after (D) 3 weeks on treatment, (F) 9 weeks on treatment, and (H) 15 weeks on treatment. Panels (E), (G), and (I) show the Western blot data for pSer935 LRRK2, total LRRK2, and GAPDH from each time point. MLi-2 treatment started at 5 weeks of age. N = 10 mice/group per time point. Data are mean ± S.E.M.; n = 10 per treatment group; *P < 0.001 compared with the vehicle diet–treated animals.

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    Fig. 6.

    Chronic in-diet dosing with MLi-2 (30 mg/kg per day) does not attenuate the behavioral phenotype in in MitoPark mice. Effect of MLi-2 on (A) distance traveled (B) rearing measured for 60 minutes. MLi-2 treatment started at 5 weeks of age. Data are mean ± S.E.M.; n = 10 per treatment group. *P < 0.05; ***P < 0.001 compared with the vehicle diet–treated animals.

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    Fig. 7.

    Effect of chronic in-diet dosing with MLi-2 (30 mg/kg per day) on LRRK2 kinase activity and histology in lung and kidney of MitoPark mice. (A) Representative Western blot data for the effect of MLi-2 on pSer935 LRRK2 and total LRRK2 in the lung and kidney of MitoPark mice. Quantification is shown in (B) for lung pSer935, in (C) for lung total LRRK2, in (D) for kidney pSer935, and in (E) for kidney total LRRK2. Mice were euthanized at 20 weeks of age, 15 weeks after treatment started. Lung histology images from vehicle- (F) and MLi-2- (G) treated MitoPark mice. MLi-2 treatment at 30 mg/kg per day for 15 weeks was associated with very slight enlargement of randomly scattered alveolar epithelial cells that had features consistent with type II pneumocytes. Kidney histology images from vehicle- (H) and MLi-2- (I) treated MitoPark mice. No accumulation of pigment in renal cortical tubules was observed in the vehicle- (H) or MLi-2- (I) treated MitoPark mice. Histology of the lung and kidney was performed at 20 weeks of age, 15 weeks after treatment started, and on n = 5 mice per treatment group. Representative images for the vehicle-treated wild-type littermate group are not shown; **P < 0.01, ***P < 0.001 compared with the vehicle-treated wild-type group.

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    TABLE 1

    Pharmacokinetic and oral bioavailability data for MLi-2 in micea

    Parameter2 mg/kg IV10 mg/kg PO
    AUC (μM⋅h)0.664 (7%)1.50 (52%)
    Cmax (μM)0.716 (11%)0.298 (72%)
    Tmax (h)0.75 (58%)
    MRT (h)2.7 (17%)11 (63%)
    %F45 (52%)
    • AUC, area under the curve; Cmax, maximum observed drug concentration; Tmax, time to maximum observed drug concentration; MRT, mean residence time; %F, oral bioavailability.

    • ↵a Values are presented as mean (CV%), N = 3.

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    TABLE 2

    Effect of chronic in-diet dosing with MLi-2 (30 mg/kg per day) on dopamine, DOPAC, HVA, and TH levels in striatum of MitoPark mice

    WeekGenotypeDoseDADOPACHVAMetabolite/DA RatioTH
    mg/kg per dayng/gng/gng/g% control
    8Wild-type01715 ± 50.7114502 ± 652.1270.0± 6.49.083 ± 0.8100.0 ± 24.7
    MitoPark01110 ± 53.4***9625 ± 332.8***263.5 ± 8.59.044 ± 0.454.56 ± 10.2
    MitoPark301114 ± 124.6***8966 ± 375.4***267.6 ± 8.38.332 ± 0.249.89 ± 10.4
    14Wild-type02175 ± 232.620076 ± 1371391.8 ± 53.39.864 ± 0.6100.0 ± 19.8
    MitoPark01037 ± 93.1***6193 ± 533.3***310.1 ± 21.56.306 ± 0.2***36.70 ± 4.7***
    MitoPark301105 ± 176.2***7521 ± 2145***323.7 ± 36.76.556 ± 0.5***42.60 ± 7.1***
    • Data are expressed as the mean and ± S.E.M. ***P < 0.001 compared with the vehicle-treated wild-type group.

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Journal of Pharmacology and Experimental Therapeutics: 355 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 3
1 Dec 2015
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Research ArticleNeuropharmacology

MLi-2, a Potent and Selective Inhibitor of LRRK2

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587

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Research ArticleNeuropharmacology

MLi-2, a Potent and Selective Inhibitor of LRRK2

Matthew J. Fell, Christian Mirescu, Kallol Basu, Boonlert Cheewatrakoolpong, Duane E. DeMong, J. Michael Ellis, Lynn A. Hyde, Yinghui Lin, Carrie G. Markgraf, Hong Mei, Michael Miller, Frederique M. Poulet, Jack D. Scott, Michelle D. Smith, Zhizhang Yin, Xiaoping Zhou, Eric M. Parker, Matthew E. Kennedy and John A. Morrow
Journal of Pharmacology and Experimental Therapeutics December 1, 2015, 355 (3) 397-409; DOI: https://doi.org/10.1124/jpet.115.227587
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