Design and synthesis of novel N-sulfonyl-2-indoles that behave as 5-HT receptor ligands with significant selectivity for D over D receptors.

All clinically-used antipsychotics display similar affinity for both D (D2R) and D (D3R) receptors, and they likewise act as 5-HT receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D and 5-HT (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.