A new class of selective, non-basic 5-HT2A receptor antagonists |
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Authors: | Ladduwahetty Tammy Boase Amanda L Mitchinson Andrew Quin Caroline Patel Smita Chapman Kerry MacLeod Angus M |
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Affiliation: | The Neuroscience Centre, Merck Sharp & Dohme, Eastwick Road, Harlow, Essex CM20 2QR, UK. Tammy.Ladduwahetty@glpg.com |
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Abstract: | 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. |
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