5HT2B receptor antagonists: a probe for spotting the pharmacophore

Serotonin (5-hydroxytryptamine, 5-HT) mediates a wide range of pharmacological effects in the central and peripheral nervous systems. Advances in molecular biological techniques have led to the identification of seven classes of 5-HT receptor subtypes (5-HT1 – 5-HT7).1 The 5-HT2 family comprises the 5-HT2A, 5-HT2B and 5-HT2C subtypes, grouped in the same class on the basis of primary structure, signal transduction characteristics, and operational profile.2 Sequence analysis indicate approximately 80% amino acid homology in the seven transmembrane domains of the three receptors.3-5 Therefore, it is not surprising that many compounds once thought to be selective for the 5-HT2A receptor also bind with high affinity to the 5-HT2B and 5-HT2C subtypes. In the last few years some antagonists which begin to differentiate among the 5-HT2 subtypes – i. e. pyridylureas 1-2, indolylisothiazolylurea 3 and tetrahydro--carboline 4 (5-HT2B selective6,7) - , have been discovered. After a careful examination of these compounds can be hypothesized that the 3-pyridylurea, the 5-isothiazolylurea and the indole moieties share structural features which can affect the interaction with the 5-HT2B receptor. Thus, considering the structure of tetrahydro--carboline 4 and on the basis of previous considerations we have hypothesized that compounds originating from the general structure 5 may be useful tools to identify the structural requirements of 5-HT2B antagonists and to disclose the 5-HT2B receptor antagonist pharmacophore. All compounds were characterized by determination of binding affinities for 5-HT2A and 5-HT2C subtypes and antagonistic activity for 5-HT2B receptor in rat stomach fundus. The results will be discussed.