Multitarget Derivatives of D2AAK1 as Potential Antipsychotics: The Effect of Substitution in the Indole Moiety

Abstract

Schizophrenia is a complex disease which is best treated with multitarget drugs, such as atypical antipsychotics. Previously, using structure-based virtual screening, we found a virtual hit, D2AAK1, with nanomolar affinity for dopamine and serotonin receptors important in schizophrenia pharmacotherapy. As a part of an optimization campaign of D2AAK1, we obtained 17 derivatives that also display a multitarget profile. Selected compounds were tested against off-targets in schizophrenia, i. e., histamine H 1 receptor and muscarinic M 1 receptor, and these did not display considerable affinity for these receptors. The two most promising compounds were subjected to behavioral studies. These compounds decreased amphetamineinduced hyperactivity in mice which indicates their antipsychotic potential. The compounds did not interfere with the memory consolidation in mice, as determined in the passive avoidance test. The favorable pharmacological profile of these compounds was rationalized using molecular modeling.

Synthesis, Structural and Behavioral Studies of Indole Derivatives D2AAK5, D2AAK6 and D2AAK7 as Serotonin 5-HT1A and 5-HT2A Receptor Ligands

“…Molecular docking revealed the classical binding pose of the ligands in the orthosteric binding pocket of the receptor with Asp 3.32 as the main anchoring point [ 22 , 23 ]. The binding pose of all the ligands in both receptors was similar: the indole moiety of the ligand penetrated deeply into the hydrophobic microdomain of the receptor [ 24 ], which was earlier observed for similar ligand–receptor complexes [ 5 , 6 , 8 , 9 , 10 , 25 ]. MM/GBSA calculations allowed one to evaluate the ligand–receptor binding energy.…”

“…In case of all ligand-receptor complexes, the indole moiety penetrates deeply into the receptor cavity interacting with the residues of the hydrophobic microdomain typical, i.a., for serotonin and dopamine receptor ligands [ 24 ]. These residues include Trp 6.48, Phe 6.51, and Phe 6.52 and hydrophobic interactions with them were observed for many similar ligand–receptor complexes [ 5 , 6 , 8 , 9 , 10 , 25 ]. Regarding complexes of D2AAK5 and D2AAK6 with serotonin 5-HT 1A receptor, an additional hydrogen bond between nitrogen hydrogen from the indole moiety of the ligands and a side chain of Ser 5.43 was observed (see Figure 4 A,B or Figure 4 C,D, respectively).…”

“…The 3D structures of D2AAK5, D2AAK6 and D2AAK7 were modelled using LigPrep module [ 47 ] of Schrödinger suite of software, v. 2019-4 as previously reported [ 7 , 8 ]. For D2AAK6 and D2AAK7 ligands, which possess a chiral carbon atom, R enantiomer was arbitrarily taken for calculations.…”

“…X-ray structure of serotonin 5-HT 2A receptor in inactive conformation in complex with an antagonist risperidone (PDB ID: 6A93 [ 49 ]) and cryo-EM structure serotonin 5-HT 1A receptor in active conformation in complex with a partial agonist aripiprazole (PDB ID: 7E2Z [ 50 ]) were used as previously reported [ 7 , 8 ]. The structures of the receptors were preprocessed using the Protein Preparation Wizard of Maestro Release 2019.4 [ 51 ], as previously reported [ 7 , 8 ]. Yasara Structure v. 20.12.24 [ 52 ] tool for loop modelling was used to build receptors extracellular loops if necessary.…”

“…Searching for novel CNS active drugs, we performed structure-based virtual screening [ 5 ] and identified a number of potential antipsychotics acting through dopamine and serotonin receptors. D2AAK1 [ 6 ] and its derivatives [ 7 , 8 ], D2AAK3 [ 9 ], and D2AAK4 [ 10 ] display antipsychotic activity in animal models as they decrease amphetamine-induced hyperactivity. Moreover, all these compounds display pro-cognitive properties and some of them have anxiolytic and antidepressant activity.…”