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Spiperone: Influence of Spiro Ring Substituents on 5-HT 2A Serotonin Receptor Binding

1998; American Chemical Society; Volume: 41; Issue: 25 Linguagem: Inglês

10.1021/jm980452a

1520-4804

Kamel Metwally, Małgorzata Dukat, Christina Egan, Carol Smith, Ann DuPre, Colleen B. Gauthier, Katharine Herrick‐Davis, Milt Teitler, Richard A. Glennon,

Neurotransmitter Receptor Influence on Behavior

Spiperone (1) is a widely used pharmacological tool that acts as a potent dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A antagonist. Although spiperone also binds at 5-HT2C receptors, it is one of the very few agents that display some (ca. 1000-fold) binding selectivity for 5-HT2A versus 5-HT2C receptors and, hence, might serve as a useful template for the development of novel 5-HT2A antagonists if the impact of its various substituent groups on binding was known. In the present investigation we focused on the 1, 3,8-triazaspiro[4.5]decanone portion of spiperone and found that replacement of the N1-phenyl group with a methyl group only slightly decreased affinity for cloned rat 5-HT2A receptors. However, N1-methyl derivatives displayed significantly reduced affinity for 5-HT1A, 5-HT2C, and dopamine D2 receptors. Several representative examples were shown to behave as 5-HT2 antagonists. As such, N1-alkyl analogues of spiperone may afford entry into a novel series of 5-HT2A-selective antagonists.