Electron Donor–Acceptor Properties of Different Muscarinic Ligands: On the Road to Control Schizophrenia

Abstract

Schizophrenia is a severe neuropsychiatric disorder that deteriorates perception, affection, and cognitive mental functions. The current treatments are mainly focused on the dopamine system, but the so-named dopamine hypothesis of schizophrenia fails to explain all the symptoms. Previous studies have shown that there is a reciprocal relationship between muscarinic acetylcholine receptors and dopamine receptor function. Some muscarinic ligands show antidopaminergic activity, and therefore, they should have some antipsychotic efficacy. In this work, conceptual density functional theory is employed to analyze the properties of acetylcholine’s agonists, partial agonists, or antagonists. The aim is to establish a classification of the antipsychotic-like or pro-psychotic activities of these molecules based on the electron-donor and electron-acceptor properties. Most of the agonists and antagonists are better electron donors and worse electron acceptors than partial agonists. We found that acetylcholine antagonists that clinically promote psychotic symptoms are good electron-donor molecules, and acetylcholine agonists that clinically relieve symptoms of psychosis are good electron donors. These results represent a further advance on the road to understanding the charge-transfer properties of drugs used as possible treatments for schizophrenia.

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“…Propenylphenothiazine is a potent antioxidant with electron-donor capability that could prevent gray matter loss, a hallmark of SCZ and SLDs [ 188 , 189 ]. Electron-donating psychotropic drugs have been known to preserve the brain volume, suggesting that propenylphenothiazine may treat psychosis without reducing the gray matter volume.…”

“…In contrast, oxidized lipids, including 7-ketocholesterol (7KCl), form looped structures, generating membrane curvatures and pores that may trigger cell death [184]. Propenylphenothiazine is a potent antioxidant with electron-donor capability that could prevent gray matter loss, a hallmark of SCZ and SLDs [188,189]. Electron-donating psychotropic drugs have been known to preserve the brain volume, suggesting that propenylphenothiazine may treat psychosis without reducing the gray matter volume.…”