The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs

Abstract

Arylsulfonyl analogs of aminopyrimidines (e.g. Ro 04-6790; 2), aminopyridines (e.g. Ro 63-0563; 3), 1-phenylpiperazines (e.g. SB-271046; 4), and tryptamines (e.g. MS-245; 5) were described as the first examples of selective 5-HT(6) receptor antagonists only ten years ago. Today, hundreds of compounds of seemingly diverse structure have been reported. The early antagonists featured an arylsulfonyl group leading to the wide notspread assumption that an arylsulfonyl moiety might be critical for binding and antagonist action. With respect to the arylsulfonyltryptamines, it seems that neither the "arylsulfonyl" nor the "tryptamine" portion of these compounds is essential for binding or for antagonist action, and some such derivatives even display agonist action. The present review describes many of the currently available 5-HT(6) receptor ligands and, unlike prior reviews, provides a narrative of the thinking (where possible) that led to their design, synthesis, and evaluation. The arylsulfonyltryptamines are also used as the structural basis of attempts to relate various structure-types to one another to afford a better understanding of the overall structural requirements for 5-HT(6) receptor binding.

Figure 1

A proposed binding mode of MS-245 (5) at the h5-HT₆ receptor looking through the extracellular side of the helical bundle. Transmembrane helix 5 (TM5), TM6, and TM7 are nearest the viewer. MS-245 is rendered as a ball-and-stick model and the heavy atoms of side chain residues whose heavy atoms fall within 3 Å of a ligand heavy atom are shown as capped sticks. The model was generated as previously reported [16] but represents a different view. Note that the terminal amine of MS-245 is within 2.7 Å of Asp106 (D106) whereas the sulfonyl oxygen atoms are within hydrogen bond distance to Ser111 (S111) on TM3 and Thr-196 on TM4 (not shown in this view). Greater detail and discussion are available [16].