Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism

Ralph N Harris 3rd; Russel S Stabler; David B Repke; James M Kress; Keith A Walker; Renee S Martin; Julie M Brothers; Mariola Ilnicka; Simon W Lee; Tara Mirzadegan

doi:10.1016/j.bmcl.2010.03.110

Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism

Bioorg Med Chem Lett. 2010 Jun 1;20(11):3436-40. doi: 10.1016/j.bmcl.2010.03.110. Epub 2010 Apr 1.

Authors

Ralph N Harris 3rd¹, Russel S Stabler, David B Repke, James M Kress, Keith A Walker, Renee S Martin, Julie M Brothers, Mariola Ilnicka, Simon W Lee, Tara Mirzadegan

Affiliation

¹ Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304, USA.

PMID: 20434910
DOI: 10.1016/j.bmcl.2010.03.110

Abstract

A series of 5-HT(6) ligands derived from (R)-1-(amino)methyl-6-(phenyl)sulfonyltetralin was prepared that yielded several non-basic analogs having sub-nanomolar affinity. Ligand structure-activity relationships, receptor point mutation studies, and molecular modeling of these novel ligands all combined to reveal a new alternative binding mode to 5-HT(6) for antagonism.

MeSH terms

Ligands
Models, Molecular
Mutagenesis, Site-Directed
Receptors, Serotonin / metabolism*
Structure-Activity Relationship

Substances

Ligands
Receptors, Serotonin
serotonin 6 receptor