Effect of N-Alkylation on the Affinities of Analogs of Spiperone for Dopamine D2 and Serotonin 5-HT2 Receptors

Robert H. Mach, Joseph R. Jackson, Robert R. Luedtke, Kathryn J. Ivins, Perry B. Molinoff, Richard L. Ehrenkaufer

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Two series of N-substituted spiperone analogues were prepared and evaluated in vitro to measure their affinities for dopamine D2 and serotonin 5-HT2 receptors. Substitution of the amide nitrogen with an alkyl group of five carbon units or less resulted in analogues displaying a low selectivity for D2 compared to 5-HT2 receptors. However, a moderate improvement in selectivity for D2 receptors was observed with N-benzylspiperone. Substitution at either the ortho or para position of the benzyl group resulted in a further reduction in affinity for 5-HT2 receptors and improvement in the selectivity ratio. Examination of N-substituted analogues of spiperone may provide insights into the topography of the antagonist binding region of the 5-HT2 receptor. The results also suggest that an 18F-labeled analogue of N-(4-nitrobenzyl)spiperone (4p) may be a suitable tracer for studying D2 receptors with positron emission tomography since this compound displays a high selectivity for D2 receptors relative to that of spiperone and N-methylspiperone.

Original languageEnglish
Pages (from-to)423-430
Number of pages8
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - 1 Feb 1992


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