In Vivo Characterization of a Dual Adenosine A2A/A1 Receptor Antagonist in Animal Models of Parkinson's Disease

被引：52

作者：

Shook, Brian C. ^{[1
]}

Rassnick, Stefanie ^{[1
]}

Osborne, Melville C. ^{[1
]}

Davis, Scott ^{[1
]}

Westover, Lori ^{[1
]}

Boulet, Jamie ^{[1
]}

Hall, Daniel ^{[1
]}

Rupert, Kenneth C. ^{[1
]}

Heintzelman, Geoffrey R. ^{[1
]}

Hansen, Kristin ^{[1
]}

Chakravarty, Devraj ^{[1
]}

Bullington, James L. ^{[1
]}

Russell, Ronald ^{[1
]}

Branum, Shawn ^{[1
]}

Wells, Kenneth M. ^{[1
]}

Damon, Sandra ^{[1
]}

Youells, Scott ^{[1
]}

Li, Xun ^{[1
]}

Beauchamp, Derek A. ^{[1
]}

Palmer, David ^{[1
]}

Reyes, Mayra ^{[1
]}

Demarest, Keith ^{[1
]}

Tang, Yuting ^{[1
]}

Rhodes, Kenneth ^{[1
]}

Jackson, Paul F. ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 22期

关键词：

HUMAN BRAIN; SUBSTANTIA-NIGRA; DOPAMINE; POTENT; RAT; ARYLINDENOPYRIMIDINES; NEUROPROTECTION; LOCALIZATION; INHIBITION; DYSKINESIA;

D O I：

10.1021/jm100971t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The in vivo characterization of a dual adenosine A(2A)/A(1) I receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of I from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K-i = 4.1 nM A(1) K-i = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

引用

页码：8104 / 8115

页数：12

共 59 条

[1] A reassessment of risks and benefits of dopamine agonists in Parkinson's disease [J].

Antonini, Angelo ;

Tolosa, Eduardo ;

Mizuno, Yoshikuni ;

Yamamoto, Mitsutoshi ;

Poewe, Werner H. .

LANCET NEUROLOGY, 2009, 8 (10) :929-937

[2] Behavioural Adverse Effects of Dopaminergic Treatments in Parkinson's Disease Incidence, Neurobiological Basis, Management and Prevention [J].

Antonini, Angelo ;

Cilia, Roberto .

DRUG SAFETY, 2009, 32 (06) :475-488

[3] EFFECT OF LOCALLY INFUSED 2-CHLOROADENOSINE, AN A1 RECEPTOR AGONIST, ON SPONTANEOUS AND EVOKED DOPAMINE RELEASE IN RAT NEOSTRIATUM [J].

BALLARIN, M ;

REIRIZ, J ;

AMBROSIO, S ;

MAHY, N .

NEUROSCIENCE LETTERS, 1995, 185 (01) :29-32

[4]

BANKIEWICZ KS, 1991, METH NEUROSCI, V7, P168

[5] Adenosine A2A receptor antagonist treatment of Parkinson's disease [J].

Bara-Jimenez, W ;

Sherzai, A ;

Dimitrova, T ;

Favit, A ;

Bibbiani, F ;

Gillespie, M ;

Morris, MJ ;

Mouradian, MM ;

Chase, TN .

NEUROLOGY, 2003, 61 (03) :293-296

[6] Quantitative evaluation of MPTP-treated nonhuman parkinsonian primates in the HALLWAY task [J].

Campos-Romo, Aurelio ;

Ojeda-Flores, Rafael ;

Moreno-Briseno, Pablo ;

Fernandez-Ruiz, Juan .

JOURNAL OF NEUROSCIENCE METHODS, 2009, 177 (02) :361-368

[7] Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease [J].

Chen, JF ;

Xu, K ;

Petzer, JP ;

Staal, R ;

Xu, YH ;

Beilstein, M ;

Sonsalla, PK ;

Castagnoli, K ;

Castagnoli, N ;

Schwarzschild, MA .

JOURNAL OF NEUROSCIENCE, 2001, 21 (10) :art. no.-RC143

[8] L-DOPA ESTERS AS POTENTIAL PRODRUGS .3. BEHAVIORAL ACTIVITY IN EXPERIMENTAL-MODELS OF PARKINSONS-DISEASE [J].

COOPER, DR ;

MARREL, C ;

VANDEWATERBEEMD, H ;

TESTA, B ;

JENNER, P ;

MARSDEN, CD .

JOURNAL OF PHARMACY AND PHARMACOLOGY, 1987, 39 (08) :627-635

[9] The substantia nigra of the human brain - II. Patterns of loss of dopamine-containing neurons in Parkinson's disease [J].

Damier, P ;

Hirsch, EC ;

Agid, Y ;

Graybiel, AM .

BRAIN, 1999, 122 :1437-1448

[10] The role and regulation of adenosine in the central nervous system [J].

Dunwiddie, TV ;

Masino, SA .

ANNUAL REVIEW OF NEUROSCIENCE, 2001, 24 :31-55

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