The text describes the comparative study of three compounds,
S 18126,
L 745,870, and
raclopride, on various
dopamine receptors and their effects in different models. S 18126 demonstrated a significantly higher affinity for the human
D4 receptor compared to other receptors, with a Ki value of 2.4 nM, while L 745,870 showed a similar selectivity with a Ki of 2.5 nM. In contrast, raclopride had low affinity for the D4 receptor but was potent at
D2 and D3 receptors.
Both S 18126 and L 745,870 effectively blocked dopamine-induced [35S]-GTPγS binding at the D4 receptor with low Kb values, whereas raclopride was inactive. Conversely, raclopride was effective in inhibiting the
D2 receptor, while the other two compounds were not.
Raclopride significantly increased dopamine synthesis in various pathways and showed strong effects in multiple models of antipsychotic activity and motor symptoms. However, S 18126 and L 745,870 were less active in these models, even at high doses.
In terms of postsynaptic effects, raclopride reduced rotational behavior and hyperlocomotion, among other effects, while S 18126 and L 745,870 were again less potent. Raclopride also increased dopamine levels in the frontal cortex, accumbens, and striatum, but S 18126 and L 745,870 did not alter these levels at the same dose. At a higher dose, S 18126 increased dopamine and noradrenaline in the frontal cortex without affecting other areas.
The conclusion is that S 18126 and L 745,870 are potent and selective D4 antagonists in vitro, but their in vivo effects at high doses may be due to residual actions at D2 or D3 receptors. The study suggests that selective D4 blockade does not modify dopaminergic transmission or confer antipsychotic or extrapyramidal effects, and further research is needed to understand the functional impact of D4 receptor blockade.
How to Use Synapse Database to Search and Analyze Translational Medicine Data?
The transational medicine section of the Synapse database supports searches based on fields such as drug, target, and indication, covering the T0-T3 stages of translation. Additionally, it offers a historical conference search function as well as filtering options, view modes, translation services, and highlights summaries, providing you with a unique search experience.

Taking obesity as an example, select "obesity" under the indication category and click search to enter the Translational Medicine results list page. By clicking on the title, you can directly navigate to the original page.

By clicking the analysis button, you can observe that GLP-1R treatment for obesity has gained significant attention over the past three years, with preclinical research still ongoing in 2023. Additionally, there are emerging potential targets, such as GDF15, among others.

Click on the image below to go directly to the Translational Medicine search interface.
