MR33317 is an experimental drug (below structural formula), initially developed to treat Alzheimer’s disease because it can stimulate brain 5-HT₄ receptors (K_i = 42 nM, 36 % agonism) and inhibit cholinesterase activity in the brain (IC₅₀ = 41 nM).

These actions are thought to increase brain concentrations of acetylcholine. Increased brain levels of acetylcholine are probably able to inhibit the progress of the Alzheimer’s disease. However, in clinical studies, other 5-HT₄ receptor agonists turned out to stimulate also cardiac 5-HT₄ receptors and thereby increasing beating rate in the sinus node. Hence, in this study, we wanted to test MR33317 in human hearts. To this end, we used electrically stimulated (1 Hz) human right atrial preparations obtained from patients that underwent cardiac bypass surgery. We noted that MR33317 alone, cumulative (1 µM, 3 µM, 10 µM) applied, failed to increase force of contraction. Only when 1 µM cilostamide, a phosphodiesterase III inhibitor, was given first to raise force of contraction, additionally applied MR33317 (10 µM) increased force of contraction in human right atrial preparations. The positive inotropic effect of MR33317 in human right atrial preparations was attenuated by 10 µM tropisetron, which was used here as a 5-HT₄ receptor antagonist. We conclude that MR33317 can activate 5-HT₄ receptors in the isolated human atrium. This effect is probably cAMP mediated. It remains to be established, whether therapeutic drug levels of MR33317 will be high enough to lead to overstimulation of 5-HT₄ receptors and subsequent cardiac arrhythmias.