Imidazopyridine-Based 5-HT₆ Receptor Neutral Antagonists: Impact of N¹-Benzyl and N¹-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 7e, which acts as a potent 5-hydroxytryptamine type 6 receptor (5-HT 6 R) neutral antagonist at Gs and does not impact neurite growth (process controlled by Cdk5). MD simulations highlighted receptor conformational changes for 7e and inverse agonist PZ-1444. In cell-based assays, neutral antagonists of the 5-HT 6 R (7e 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-HT 6 R with neutral antagonists implicates the protecting properties of astrocytes. Additionally, 7e prevented scopolamine-induced learning deficits in the novel object recognition test in rats. We propose 7e as a probe for further understanding of the functional outcomes of different states of the 5-HT 6 R.

2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity

“…Selectivity Profiles of Selected Compounds. The most potent compounds (K i ≤ 30 nM) exhibiting structural (18,22,28) and enantiomeric (27,28) diversity were further evaluated for their selectivity over serotonin receptors (5-HT 1A R, 5-HT 2A R, 5-HT 7 R) and dopamine D 2 receptor (D 2 R) in radioligand binding assays. The tested compounds displayed high selectivity over 5-HT 1A , 5-HT 2A , 5-HT 7 , and D 2 receptors (Table 2).…”

“…The synthetic procedures for intermediates 5 and 6 and final compounds (7−32) as well as characterization data for selected final compounds (18,22,27,28) are presented below. The synthesis of intermediates 1−4 was performed according to the previously described procedures 19,20 and is reported in the Supporting Information together with spectroscopic data for all intermediates and remaining final compounds.…”

“…Our recent interest in 5-HT 6 R ligands has culminated in the identification of ( S )-1-[(3-chlorophenyl)­sulfonyl]-4-(pyrrolidine-3-yl-amino)-1 H -pyrrolo­[3,2- c ]­quinoline (CPPQ), a pyrroloquinoline-derived potent and selective 5-HT 6 R neutral antagonist. , Inspired by the activity of CPPQ, , we applied the scaffold-hopping approach to replace the planar 1 H -pyrrolo­[3,2- c ]­quinoline skeleton with a more flexible 2-phenyl-1 H -pyrrole-3-carboxamide in order to investigate the effect of a central core retraction on 5-HT 6 R affinity and functional activity. The chemical diversity around the new framework involved ( i ) introduction of a fluorine atom at the 2-phenyl fragment (R 1 ), ( ii ) functionalization of N 1 pyrrole with aryl- or heteroarylsulfonyl moieties (R 2 ), and ( iii ) changing configuration at the 3-aminopyrrolidinyl moiety at the 3-carboxamide fragment (Figure ).…”

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties

“…5-HT 6 R antagonists improve cognitive performance in a wide range of preclinical models of cognitive impairment. 19 − 21 The beneficial effects of 5-HT 6 R antagonists on cognition have been attributed to the enhanced release of acetylcholine and glutamate in the frontal cortex and hippocampus. 22 , 23 Finally, the selective 5-HT 6 R antagonists—idalopirdine and AVN-211—have advanced to phase II and phase IIa clinical trials, respectively, as add-on therapies against schizophrenia, but the results were not conclusive.…”

“…Recent studies on the 5-HT 6 R interactome identified additional signaling pathways, including the Fyn tyrosine kinase, mechanistic target of rapamycin (mTOR, involved in synaptic plasticity and cognition), and cyclin-dependent kinase 5 (Cdk5) pathway, which is critical for neuron migration and neurite growth. 5-HT 6 R antagonists improve cognitive performance in a wide range of preclinical models of cognitive impairment. − The beneficial effects of 5-HT 6 R antagonists on cognition have been attributed to the enhanced release of acetylcholine and glutamate in the frontal cortex and hippocampus. , Finally, the selective 5-HT 6 R antagonistsidalopirdine and AVN-211have advanced to phase II and phase IIa clinical trials, respectively, as add-on therapies against schizophrenia, but the results were not conclusive. , …”