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

Authors: Glennon, R.A.; Metwally, K.; Dukat, M.; Ismaiel, A.M.; Los Angeles, J.; Herndon, J.; Teitler, M.; Khorana, N.

Source: Current Topics in Medicinal Chemistry, Volume 2, Number 6, 1 June 2002 , pp. 539-558(20)

Publisher: Bentham Science Publishers

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Abstract:

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.

Keywords: Ketanserin and Spiperone; Serotonin 5-HT2A; KETANSERIN ANALOGS; Quinazoline-Abbreviated Analogs; Benzoylpiperidine

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568026023393787

Publication date: 2002-06-01