Analysis of the actions of the novel dopamine receptor-directed compounds (S)-OSU6162 and ACR16 at the D-2 dopamine receptor

作者：Kara Elodie; Lin Hong; Svensson Kjell; Johansson Anette M; Strange Philip G^*

来源：British Journal of Pharmacology, 2010, 161(6): 1343-1350.

DOI：10.1111/j.1476-5381.2010.01010.x

• OSU6162
• ACR16
• dopamine stabilizers
• D-2 dopamine receptor
• radioligand binding
• stimulation of [35S]GTP gamma S binding
• allosteric effects

BACKGROUND AND PURPOSE
The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D-2 dopamine receptor in vitro.
EXPERIMENTAL APPROACH
The affinities of these compounds for the D-2 dopamine receptor were evaluated in competition with [3H]spiperone and [3H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [35S]GTP gamma S binding.
KEY RESULTS
Both compounds had low affinities for inhibition of [3H]spiperone binding (pK(i) vs. [3H]spiperone, ACR16: < 5, OSU6162: 5.36). Neither compound was able to stimulate [35S]GTP gamma S binding when assayed in the presence of Na+ ions, but if the Na+ ions were removed, both compounds were low-affinity, partial agonists (E-max relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [35S]GTP gamma S binding indicated Schild slopes of similar to 0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [3H]NPA dissociation from D-2 dopamine receptors, indicating some allosteric effects of this compound.
CONCLUSIONS AND IMPLICATIONS
The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D-2 dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed.
LINKED ARTICLES
This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

• 出版日期2010-11