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

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journal contribution
posted on 13.10.2011, 00:00 by Balázs Volk, István Gacsályi, Katalin Pallagi, László Poszávácz, Ildikó Gyönös, Éva Szabó, Tibor Bakó, Michael Spedding, Gyula Simig, Gábor Szénási
A series of (arylpiperazinylbutyl)oxindoles as highly potent 5-HT7 receptor antagonists has been studied for their selectivity toward the 5-HT1A receptor and α1-adrenoceptor. Several derivatives exhibited high 5-HT7/5-HT1A selectivity, and the key structural factors for reducing undesired α1-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.