A new class of selective, non-basic 5-HT2A receptor antagonists.
Based on an existing series of 5-HT2A receptor ligands containing a basic nitrogen, we designed a non-basic lead that had reduced affinity for both the 5-HT2A receptor and the IKr potassium channel. The present paper describes the development of this lead to a novel series of non-basic piperidine sulfonamides and amides that have high affinity for the 5-HT2A receptor, whilst maintaining excellent selectivity over off target activities such as the IKr channel. This work has shown that the proposed pharmacophore model for the 5-HT2A receptor which suggests that a basic nitrogen is required for the binding of ligands is questionable.
Ladduwahetty
Tammy
T
The Neuroscience Centre, Merck Sharp & Dohme, Eastwick Road, Harlow, Essex CM20 2QR, UK. Tammy.Ladduwahetty@glpg.com
Boase
Amanda L
AL
Mitchinson
Andrew
A
Quin
Caroline
C
Patel
Smita
S
Chapman
Kerry
K
MacLeod
Angus M
AM
D006801:Humans; D015394:Molecular Structure; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists; D013329:Structure-Activity Relationship
D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists