Investigation of the binding and functional properties of extended length D3 dopamine receptor-selective antagonists

Abstract The D3 dopamine receptor represents an important target in drug addiction in that reducing receptor activity may attenuate the self-administration of drugs and/or disrupt drug or cue-induced relapse. Medicinal chemistry efforts have led to the development of D3 preferring antagonists and pa...

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Published in:European neuropsychopharmacology 2015-09, Vol.25 (9), p.1448-1461
Main Authors: Furman, Cheryse A, Roof, Rebecca A, Moritz, Amy E, Miller, Brittney N, Doyle, Trevor B, Free, R. Benjamin, Banala, Ashwini K, Paul, Noel M, Kumar, Vivek, Sibley, Christopher D, Newman, Amy Hauck, Sibley, David R
Format: Article
Language:English
Subjects:
Allosteric
Allosteric Regulation
Animals
Arrestins - metabolism
beta-Arrestins
Binding, Competitive
Bitopic
Bivalent
CHO Cells
Cricetulus
D3 receptor
Dopamine antagonists
Dopamine Antagonists - chemistry
Dopamine Antagonists - metabolism
Dopamine Antagonists - pharmacology
Dopamine receptor
Drug Evaluation, Preclinical
Humans
Internal Medicine
Molecular Structure
Psychiatry
Radioligand Assay
Receptors, Dopamine D3 - antagonists & inhibitors
Receptors, Dopamine D3 - genetics
Receptors, Dopamine D3 - metabolism
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Summary:Abstract The D3 dopamine receptor represents an important target in drug addiction in that reducing receptor activity may attenuate the self-administration of drugs and/or disrupt drug or cue-induced relapse. Medicinal chemistry efforts have led to the development of D3 preferring antagonists and partial agonists that are >100-fold selective vs. the closely related D2 receptor, as best exemplified by extended-length 4-phenylpiperazine derivatives. Based on the D3 receptor crystal structure, these molecules are known to dock to two sites on the receptor where the 4-phenylpiperazine moiety binds to the orthosteric site and an extended aryl amide moiety docks to a secondary binding pocket. The bivalent nature of the receptor binding of these compounds is believed to contribute to their D3 selectivity. In this study, we examined if such compounds might also be “bitopic” such that their aryl amide moieties act as allosteric modulators to further enhance the affinities of the full-length molecules for the receptor. First, we deconstructed several extended-length D3 -selective ligands into fragments, termed “synthons”, representing either orthosteric or secondary aryl amide pharmacophores and investigated their effects on D3 receptor binding and function. The orthosteric synthons were found to inhibit radioligand binding and to antagonize dopamine activation of the D3 receptor, albeit with lower affinities than the full-length compounds. Notably, the aryl amide-based synthons had no effect on the affinities or potencies of the orthosteric synthons, nor did they have any effect on receptor activation by dopamine. Additionally, pharmacological investigation of the full-length D3 -selective antagonists revealed that these compounds interacted with the D3 receptor in a purely competitive manner. Our data further support that the 4-phenylpiperazine D3 -selective antagonists are bivalent and that their enhanced affinity for the D3 receptor is due to binding at both the orthosteric site as well as a secondary binding pocket. Importantly, however, their interactions at the secondary site do not allosterically modulate their binding to the orthosteric site.
ISSN:0924-977X
1873-7862
DOI:10.1016/j.euroneuro.2014.11.013