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Characterization of 125 I‐IABN, a novel azabicyclononane benzamide selective for D2‐like dopamine receptors
Author(s) -
Luedtke Robert R.,
Freeman Rebekah A.,
Boundy Virginia A.,
Martin Michael W.,
Huang Yunsheng,
Mach Robert H.
Publication year - 2000
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/1098-2396(20001215)38:4<438::aid-syn9>3.0.co;2-5
Subject(s) - benzamide , dopamine , dopamine receptor d2 , chemistry , receptor , dopamine receptor , neuroscience , biology , biochemistry , stereochemistry
The properties of an 125 I‐labeled structural analog of 2,3‐dimethoxy‐N‐[9‐(4‐fluorobenzyl)‐9‐azabicyclo[3.3.1]nonan‐3β‐yl]benzamide (MABN), 125 I‐IABN, are described. 125 I‐IABN was developed as a high‐affinity radioligand selective for the D2‐like (D2, D3, and D4) dopamine receptor subtypes. 125 I‐IABN binds with picomolar affinity and nonselectively to rat D2 and D3 dopamine receptors expressed in Sf9 and HEK 293 cells. 125 I‐IABN binds with 7‐ to 25‐fold lower affinity to human D4.4 dopamine receptors expressed in HEK 293 cells. Dissociation constants ( Kd ) calculated from kinetic experiments were in agreement with equilibrium Kd values obtained from saturation binding studies. Saturation plots of the binding of 125 I‐IABN with rat caudate membrane preparations were monophasic and exhibited low nonspecific binding. The pharmacologic profile of the binding of 125 I‐IABN to rat caudate was consistent with a D2‐like receptor, suggesting that the ligand binds primarily to D2 dopamine receptors. In addition, IABN was found to bind with low affinity to D1 dopamine receptors, as well as to the σ1 and σ2 receptor subtypes. Quantitative autoradiographic studies using rat brain slices indicate that 125 I‐IABN selectively labels the striatum and the olfactory tubercle area, which is consistent with the labeling of D2‐like receptors. IABN blocks dopamine‐dependent inhibition of adenylyl cyclase activity at D2 or D4.4 receptors expressed in HEK cells. Therefore, 125 I‐IABN appears to be a high‐affinity, selective antagonist at D2‐like dopamine receptors. Finally, a unique property of the azabicyclononane benzamide 125 I‐IABN compared to previously studied substituted benzamides is that the binding of this radioligand is not effected by variations in Na + concentration. Synapse 38:438–449, 2000. © 2000 Wiley‐Liss, Inc.