Novel 3-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole-based multifunctional ligands with antipsychotic-like, mood-modulating, and procognitive activity

The takeaway

Compound 16, a newly discovered indole-based ligand, demonstrated antipsychotic-, antidepressant-, anxiolytic-like, and procognitive effects in mice, with a superior safety profile compared to standard medications.

The science

Compound 16 was designed to act as a multitarget ligand, with partial agonist activity at dopamine D₂ receptors, antagonist activity at serotonin 5-HT₆ and 5-HT₇ receptors, activation of 5-HT_1A receptors, and blocking of serotonin reuptake. In mice, it showed antipsychotic-like effects by reversing MK-801–induced hyperactivity, antidepressant-like effects by reducing immobility in the forced swim test, and anxiety-reducing effects by increasing exploration in anxiety models. At low doses, it also improved memory in healthy mice and reversed scopolamine-induced deficits, indicating procognitive effects. Unlike aripiprazole, it didn’t cause sedation or catalepsy, and safety studies revealed a low risk of cardiac or muscarinic side effects. These findings suggest a compound that combines wide-ranging behavioral benefits with cognitive improvements and a good safety profile.

Why it matters

By bringing together broad behavioral effectiveness with cognitive advantages and a low risk of side effects, compound 16 shows promise as a treatment for behavioral and psychological symptoms of dementia (BPSD).

Original article

https://doi.org/10.1021/acs.jmedchem.7b00839