Selective Dopamine D4 Receptor Antagonism: Comparative Analysis of S 18126, L 745,870, and Raclopride

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.