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.2008 Jan 14;578(2-3):123-36.
doi: 10.1016/j.ejphar.2007.09.020. Epub 2007 Oct 2.

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones

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An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure-affinity relationship for butyrophenones

Ivan T Lee et al. Eur J Pharmacol..

Abstract

The ability of the sigma(1) receptor to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma(1) receptor ligands vary more than 50-fold. The potential of the sigma(1) receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma(1) receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D(4) receptor selective compounds bind sigma(1) receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with the sigma(1) receptor were confirmed with our screening assay.

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Figures

Fig. 1
Fig. 1
[3H]-(+)-pentazocine saturation isotherm binding to a clonal human MCF-7 cell line stably expressing the human sigma1 receptor. The average affinity (KD) and receptor density (Bmax) values (n = 3) are: 3.7 ± 0.87 nM and 109 ± 23.7 pmoles/mg protein, respectively. No specific [3H]-(+)-pentazocine binding was detected in untransfected MCF-7 cells, indicating the absence of drug-sensitive endogenous sigma1 or opioid receptors.
Fig. 2
Fig. 2
Displacement of [3H]-(+)-pentazocine binding by a sigma1 selective antagonist (BD1063) and by stereoisomers of a prototypical benzomorphan agonist (+)-SFK10,047 and (−)-SKF10,077. Binding studies utilized cell homogenates derived from membranes of MCF-7 cells stably expressing the human sigma1 receptor. The affinity values (Ki) are listed in Table 1.
Fig. 3
Fig. 3
Displacement of [3H]-(+)-pentazocine binding by butyrophenones and reduced haloperidol. Butyrophenone class compounds bind to the sigma1 receptor with varying degrees of affinity. Reduced haloperidol exhibits similar binding as haloperidol. The affinity values (Ki) are listed in Table 1.
Fig. 4
Fig. 4
Displacement of [3H]-(+)-pentazocine binding by dopamine D4 receptor selective compounds. Several dopamine D4 receptor selective drugs also bind to sigma1 receptors with a range of affinities. The rank order for these drug affinities is: RBI-257 >> L745,870 >> PD168,077 > NGD94-1. The affinity values (Ki) are listed in Table 1.
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References

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