In
this study, a panel of 46 compounds containing five different
scaffolds known to have high σ2 receptor affinity
were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline
[(±)-7] (K
i for σ1 = 48.4 ± 7.7 nM, and K
i for
σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue,
(±)-8 (K
i for σ1 = 108 ± 35 nM, and K
i for
σ2 = 4.92 ± 0.59 nM), showed excellent binding
affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and
[11C]-(±)-8 was dependent on TMEM97 protein
expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than
that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc)
with specific distribution in the cortex and hypothalamus. Brain uptake
or tissue binding was selectively inhibited by ligands with different
σ2 receptor binding affinities. The results suggest
[11C]-(±)-7 can be used as a PET radiotracer
for imaging the function of σ2 receptors in central
nervous system disorders.
Previous studies have confirmed that the binding of D3 receptor antagonists is competitively inhibited by endogenous dopamine despite excellent binding affinity for D3 receptors. This result urges the development of an alternative scaffold that is capable of competing with dopamine for binding to the D3 receptor. Herein, an SAR study was conducted on metoclopramide that incorporated a flexible scaffold for interaction with the secondary binding site of the D3 receptor. The alteration of benzamide substituents and secondary binding fragments with aryl carboxamides resulted in excellent D3 receptor affinities (Ki = 0.8–13.2 nM) with subtype selectivity to the D2 receptor ranging from 22- to 180-fold. The β-arrestin recruitment assay revealed that 21c with 4-(pyridine-4-yl)benzamide can compete well against dopamine with the highest potency (IC50 = 1.3 nM). Computational studies demonstrated that the high potency of 21c and its analogs was the result of interactions with the secondary binding site of the D3 receptor. These compounds also displayed minimal effects for other GPCRs except moderate affinity for 5-HT3 receptors and TSPO. The results of this study revealed that a new class of selective D3 receptor antagonists should be useful in behavioral pharmacology studies and as lead compounds for PET radiotracer development.
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