Highly potent, non-basic 5-HT6 ligands. Site mutagenesis evidence for a second binding mode at 5-HT6 for antagonism.
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.
Harris
Ralph N
RN
Roche Palo Alto LLC, 3431 Hillview Ave., Palo Alto, CA 94304, USA.
Stabler
Russel S
RS
Repke
David B
DB
Kress
James M
JM
Walker
Keith A
KA
Martin
Renee S
RS
Brothers
Julie M
JM
Ilnicka
Mariola
M
Lee
Simon W
SW
Mirzadegan
Tara
T
D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D011985:Receptors, Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor