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Ketanserin and Spiperone as Templates for Novel Serotonin 5-HT2A Antagonists

[ Vol. 2 , Issue. 6 ]


Richard A. Glennon, Kamel Metwally, Malgorzata Dukat, Abd M. Ismaiel, Joseph De. Los Angeles, Jeffery Herndon, Milt Teitler and Nantaka Khorana   Pages 539 - 558 ( 20 )


The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT2A receptor affinity and selectivity. It was found that the presence of the quinazoline ring of ketanserin detracts from selectivity and that various ring-opened analogs displayed ketanserin-like affinity and up to 30-fold enhanced selectivity. The triazaspirodecanone portion of spiperone is a major determinant of its 5-HT2A affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N1-substituent, are important factors in controlling binding at 5-HT2A, 5-HT2C, 5-HT1A, and dopamine D2 receptors. Replacement of the N1-phenyl ring of spiperone with a methyl group (KML-010 48) resulted in a compound that binds at 5-HT2A receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki > 10,000 nM) for 5-HT2C and 5-HT1A receptors and binds with 400-fold reduced affinity at D2 receptors.


Ketanserin and Spiperone, Serotonin 5-HT2A, KETANSERIN ANALOGS, Quinazoline-Abbreviated Analogs, Benzoylpiperidine


Department ofMedicinal Chemistry, School of Pharmacy, Virginia CommonwealthUniversity, Richmond, VA 23298 USA

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