engleski

Compounds with phenanthridine moiety as potential modulators of butyrylcholinesterase activity

Butyrylcholinesterase (BChE, E.C. 3.1.1.8) is a serine hydrolase closely related to acetylcholinesterase (AChE ; EC 3.1.1.7). AChE is a key enzyme in the regulation of cholinergic transmission that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh). Since Alzheimer’s disease (AD) is characterized by the decline of ACh levels, drugs designed for the treatment of AD are AChE inhibitors that lead to an increase of ACh levels and alleviation of disease symptoms. Although BChE's physiological function is yet unclear, it can serve as a co-regulator of cholinergic neurotransmission due to ACh hydrolysis. Moreover, BChE plays an important role in the pathogenesis of AD due to a role in the amyloid beta-peptide aggregation developing into senile plaque deposits. It is reasonable to assume that BChE inhibition will have a beneficial impact on the medical treatment of AD patients. Selective BChE inhibitors could lead to better AD drugs. Crystal structures of AChE-inhibitor complexes have shown that AChE inhibitors usually interact with the active site amino acids via arene–arene (π-π) interactions. Even though AChE and BChE active sites have different amino acid compositions with 6 out of 14 aromatic amino acids in the AChE active site corresponding to aliphatic ones in the BChE active sites, BChE can still be considered to have significant potential for π-π interactions with inhibitors. In the search for new BChE inhibitors, we have turned our attention toward small organic molecules with phenanthridine moiety. This moiety is often applied for an ‘‘aryl’’ component due to structural features like a permanent or pH-induced positive charge, high polarizability, high electron affinity and highly polar amino groups. The property of induced positive charge may help these compounds to pass the blood-brain barrier and act in the central nervous system. Therefore, we studied the inhibition of BChE with 10-aminophenanthridine and phenanthridines substituted at the position 8 of the phenanthridine ring with biguanide, benzyl carbamate, or urea-based substituents characterized by a combination of binding and steric properties. To demonstrate the significance of positive charge on the stabilization of BChE inhibitors, we also studied the inhibition of BChE with monocationic 2-(cinnolin-4(1H)-ylidenemethyl)-4, 6-dimethylthiazolo[4, 5-b]pyridin-4-ium iodide. All of the compounds reversibly inhibited BChE with inhibition constants (Ki) in the 5–750 micromolar range.

Butyrylcholinesterase; Acetylcholinesterase; Inhibition; Phenanthridine Compounds

nije evidentirano