Imidazopyridine-Based 5-HT₆ Receptor Neutral Antagonists: Impact of <i>N</i>¹-Benzyl and <i>N</i>¹-Phenylsulfonyl Fragments on Different Receptor Conformational States

Abstract

G-protein coupled receptors (GPCRs) exist in an equilibrium of multiple conformational states, including different active states, which depend on the nature of the bound ligand. In consequence, different conformational states can initiate specific signal transduction pathways. The study identified compound <b>7e</b>, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT₆R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for <b>7e</b> and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT₆R (<b>7e</b> and CPPQ), but not inverse agonists (SB-258585, intepirdine, PZ-1444), displayed glioprotective properties against 6-hydroxydopamine-induced and doxorubicin-induced cytotoxicity. These suggest that targeting the activated conformational state of the 5-HT₆R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, <b>7e</b> prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose <b>7e</b> as a probe for further understanding of the functional outcomes of different states of the 5-HT₆R.