title: Reformulating a Pharmacophore for 5-HT2A Serotonin Receptor Antagonists.
abstract: Several pharmacophore models have been proposed for 5-HT2A serotonin receptor antagonists. These typically consist of two aromatic/hydrophobic moieties separated by a given distance from each other, and from a basic amine. Although specified distances might vary, the models are relatively similar in their general construction. Because our preliminary data indicated that two aromatic (hydrophobic) moieties might not be required for such action, we deconstructed the serotonin-dopamine antipsychotic agent risperidone (1) into four smaller structural fragments that were thoroughly examined in 5-HT2A receptor binding and functional (i.e., two-electrode voltage clamp (TEVC) and intracellular calcium release) assays. It was apparent that truncated risperidone analogues behaved as antagonists. In particular, 6-fluoro-3-(1-methylpiperidin-4-yl)benzisoxazole (4) displayed high affinity for 5-HT2A receptors (Ki of ca. 12 nM) relative to risperidone (Ki of ca. 5 nM) and behaved as a potent 5-HT2A serotonin receptor antagonist. These results suggest that multiple aromatic (hydrophobic) moieties are not essential for high-affinity 5-HT2A receptor binding and antagonist activity and that current pharmacophore models for such agents are very much in need of revision.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Younkin
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Supriya A
authors.initials: SA
authors.lastname: Gaitonde
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Amr
authors.initials: A
authors.lastname: Ellaithy
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Vekariya
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Lia
authors.initials: L
authors.lastname: Baki
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: José L
authors.initials: JL
authors.lastname: Moreno
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Sneha
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Drossopoulos
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Kelsey S
authors.initials: KS
authors.lastname: Hideshima
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Eltit
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Maeso
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Diomedes E
authors.initials: DE
authors.lastname: Logothetis
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Dukat
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, and ‡Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , Richmond, Virginia 23298, United States.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D001464:Barium / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D007650:Ketanserin / Q000493:pharmacokinetics / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009865:Oocytes; D011485:Protein Binding / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism; D018967:Risperidone / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D014316:Tritium / Q000493:pharmacokinetics; D014982:Xenopus laevis
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D014316:Tritium; D001464:Barium; D012701:Serotonin; D007650:Ketanserin; D018967:Risperidone; D002118:Calcium
keywords: 3-(4-piperidinyl)benzisoxazoles; Risperidone; TEVC (two-electrode voltage clamp); antipsychotics; calcium release