Optimization of (Arylpiperazinylbutyl)oxindoles Exhibiting Selective 5-HT7 Receptor Antagonist Activity

A series of (arylpiperazinylbutyl)oxindoles as highly potent 5-HT7 receptor antagonists has been studied for their selectivity toward the 5-HT1A receptor and alpha(1)-adrenoceptor. Several derivatives exhibited high 5-HT7/5-HT1A selectivity, and the key structural factors for reducing undesired alpha(1)-adrenergic receptor binding have also been identified. Rapid metabolism, a common problem within this family of compounds, could be circumvented with appropriate substitution patterns on the oxindole carbocycle. Contrary to expectations, none of the compounds produced an antidepressant-like action in the forced swimming test in mice despite sufficiently high brain concentrations. On the other hand, certain analogues showed significant anxiolytic activity in two different animal models: the Vogel conflict drinking test in rats and the light-dark test in mice.