1. Academic Validation
  2. Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists

Ketanserin and spiperone as templates for novel serotonin 5-HT(2A) antagonists

  • Curr Top Med Chem. 2002 Jun;2(6):539-58. doi: 10.2174/1568026023393787.
Richard A Glennon 1 Kamel Metwally Malgorzata Dukat Abd M Ismaiel Joseph De los Angeles Jeffery Herndon Milt Teitler Nantaka Khorana
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. glennon@hsc.vcu.edu
Abstract

The structures of ketanserin (1) and spiperone (2) were examined in detail to determine the role of various substituent groups on 5-HT(2A) 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-HT affinity and selectivity. The conformational rigidity imposed by the ring, as well as the nature of the N(1)-substituent, are important factors in controlling binding at 5-HT(2A), 5-HT(2C), 5-HT(1A), and dopamine D2 receptors. Replacement of the N(1)-phenyl ring of spiperone with a methyl group (KML-010; 48) resulted in a compound that binds at 5-HT(2A) receptors with slightly lower affinity than spiperone, but that lacked affinity (Ki >10,000 nM) for 5-HT(2C) and 5-HT(1A) receptors and binds with 400-fold reduced affinity at D2 receptors.

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