Synthesis and preliminary pharmacological evaluation of 2-benzyloxy substituted aryl ketones as 5-HT4 receptor antagonists

Structural modification of the 2-methoxy group and at the 4-position of the piperidine ring of the 5-HT4 partial agonist 1 led to analogues with increased affinity for the 5-HT4 receptor and loss of agonist activity. Similar modification of 2 resulted in 2-(3,5-dimethoxy) benzyloxy derivatives (23, 24, 26–28) that were found to be 5-HT4 receptor antagonists with subnanomolar affinity.