Assessment of the pharmacological properties of 5-methoxyindole derivatives at 5-HT4 receptors

Abstract

Of the compounds tested, compound 3 was the most promising 5-HT(4) receptor agonist and the results highlight the value of using human tissue in functional tests when assessing compounds for potential activity.

The 5-HT4 receptor agonist prucalopride does not facilitate cholinergic neurotransmission in circular and longitudinal smooth muscle preparations of equine mid-jejunum

“…In a tissue/species with low density and/or coupling efficiency of 5-HT 4 receptors, the effect of prucalopride might thus be weak. To exclude the option of the presence of a very small population of neuronally localized intestinal 5-HT 4 receptors in horses or a low coupling efficiency of a larger population of these receptors, a tenfold higher concentration of prucalopride was tested on the one hand and on the other the effect of 10 μM serotonin (5-HT) was tested; 5-HT is a full 5-HT 4 receptor agonist, maximally active in the concentration used in different tissues with 5-HT 4 receptors (Coupar et al, 2012). However, also 3 μM prucalopride as well as 10 μM 5-HT, the latter in conditions where all other possibly interfering 5-HT receptors were blocked, did not facilitate submaximal cholinergic contractions excluding this possibility.…”

Distribution of 5-HT3, 5-HT4, and 5-HT7Receptors Along the Human Colon

“…[41][42][43] In addition, human 5-HT receptors are considerably different in their composition as evident by the diverse splice variants in 5-HT 4 and 5-HT 7 receptors and the additional 5-HT 3 receptor subunits. 1,19,44 The function and pharmacological responses of 5-HT receptors in the intestine also varies between small animal models and humans 15,41,45,46 and therefore this study was undertaken to gain an insight to the distribution of 5-HT 3 , 5-HT 4 , and 5-HT 7 receptors expressed in the human ileum and throughout the human colon. Although subtle differences in the regional distribution of the 5-HT receptors occurred, the main differences were between the mucosal and muscular tissue layers.…”

Influence of a new 5‐HT4 receptor partial agonist, YKP10811, on visceral hypersensitivity in rats triggered by stress and inflammation

“…Tegaserod had no effects on colonic tone while YKP10811 suppressed increase in colorectal tone in inflammatory conditions and increased colonic compliance in non‐inflammatory hypersensitivity conditions suggesting a modulatory effect on colonic muscular tone. Differences in the activity of 5‐HT 4 receptor agonists on circular muscle tone has been evaluated on human, and mouse colonic strips, showing that the chemical structure of the compounds, their 5‐HT 4 receptor binding affinity and selectivity and/or their properties, partial vs full agonist, may be responsible for such differences . It is hypothesized that 5‐HT 4 receptors located on smooth muscle cell exist as homodimers and that the contractile response depends upon the potency of 5‐HT 4 receptor agonists to interact with the receptor dimer …”