Synthesis and Docking of Novel 3‐Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5‐HT_1AR/SERT

Abstract

A series of novel 3‐indolylpropyl derivatives was synthesized and evaluated for their binding affinities at the serotonin‐1A receptor subtype (5‐HT 1A R) and the 5‐HT transporter (SERT). Compounds 11b and 14b exhibited the highest affinities at the 5‐HT 1A R ( K i = 43 and 56 nM), whereas compounds 11c and 14a were the most potent analogs at the SERT ( K i = 34 and 17 nM). On the other hand, compounds 14b and 11d showed potent activity at both targets, displaying a profile that makes them promising leads for the search for novel potent ligands with a dual mechanism of action. Molecular docking studies in all the compounds unveiled relevant drug–target interactions, which allowed rationalizing the observed affinities.