Comparative 5-HT4 receptor antagonist activity of LY353433 and its active hydroxylated metabolites

LY353433 is a selective, potent, and orally active 5-HT₄ receptor antagonist with a long duration of pharmacological activity following its oral administration to rats. After oral administration of LY353433 (100 mg/kg) to rats, peak plasma concentration of the parent material was approximately 25 ng/ml and rapidly declined such that 4 h after administration, plasma concentration of the parent material was barely detectable. However, two additional peaks (LY343031 and LY343032) were observed in plasma via HPLC and subsequently identified as hydroxylated metabolites of LY353433. Peak plasma concentrations of LY343031 (approximately 50 ng/ml) and of LY343032 (approximately 150 ng/ml) were achieved within 1 h after the oral administration of LY353433. Furthermore, plasma concentrations of these metabolites were maintained for several hours and declined more slowly than plasma concentrations of the parent material. Both metabolites inhibited esophageal 5-HT₄ receptors in a concentration range similar to that observed with LY353433. In addition, the receptor selectivity profiles for LY343031 and LY343032 were similar to that of LY353433 at α₁, α₂, β, Dopamine D₁, Dopamine D₂, benzodiazapine, histamine H₁, GABA_A, 5-HT₂, and muscarinic receptors. Thus, these hydroxylated derivatives of LY353433 were potent and selective 5-HT₄ receptor antagonists in vitro. Lastly, using ex vivo esophageal relaxation to serotonin to assess 5-HT₄ receptor antagonism, these compounds were less active after oral administration to rats than LY353433. Thus, the long duration of pharmacological activity observed after oral administration of LY353433 is likely related not only to the 5-HT₄ receptor antagonist activity of the parent molecule, but also to the 5-HT₄ receptor antagonist activity associated with its two hydroxylated metabolites. Drug Dev. Res. 43:193–199, 1998. © 1998 Wiley-Liss, Inc.