Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists.
Striatal adenosine A(2A) receptors (A(2A)Rs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D(2) receptors (D(2)Rs). A(2A)Rs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1) receptors (A(1)Rs). It has been hypothesized that postsynaptic A(2A)R antagonists should be useful in Parkinson's disease, while presynaptic A(2A)R antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2A)R antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2A)R-D(2)R and A(1)R-A(2A)R heteromers to determine possible differences in the affinity of these compounds for different A(2A)R heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2A)R when co-expressed with D(2)R than with A(1)R. KW-6002 showed the best relative affinity for A(2A)R co-expressed with D(2)R than co-expressed with A(1)R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively.
National Institute on Drug Abuse, IRP, NIH, DHHS, Baltimore, Maryland, United States of America.
Marco
M
Orru
Jana
J
Bakešová
Marc
M
Brugarolas
César
C
Quiroz
Vahri
V
Beaumont
Steven R
SR
Goldberg
Carme
C
Lluís
Antoni
A
Cortés
Rafael
R
Franco
Vicent
V
Casadó
Enric I
EI
Canela
Sergi
S
Ferré
D058917:Adenosine A2 Receptor Antagonists / Q000032:analysis*; D000818:Animals; D003342:Corpus Striatum; D020820:Dyskinesias / Q000188:drug therapy; D004525:Efferent Pathways / Q000166:cytology; D008297:Male; D009474:Neurons / Q000737:chemistry; D010300:Parkinson Disease / Q000188:drug therapy; D057907:Post-Synaptic Density / Q000187:drug effects; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D017661:Receptors, Presynaptic / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*
D058917:Adenosine A2 Receptor Antagonists; D017661:Receptors, Presynaptic
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