Effects of tricyclic compounds on membrane binding of bivalent cations, activities of acetylcholinesterase and some tissue proteases.

Abstract

A tricyclic compound tetrahydroaminoacridine is known to improve the cognitive function in Alzheimer's disease. The possible mechanism of action of acridine and structurally related tricyclic compounds was studied on the bivalent cation content of bacterial membrane, rat brain acetylcholinesterase and some tissue proteases in model experiments. Acridine orange and disubstituted chlorpromazine (CPZ) derivatives lowered Ca2+ and Mg2+ binding and membrane polarization in the simplest biological membrane (E. coli), as revealed by reactor neutron activation analysis. Acetylcholinesterase (AChE) was inhibited by CPZ, 3,7,8-trihydroxy-CPZ, acridine orange partially saturated desipramine, imipramine, trans-clopenthixol and tetrahydrocannabidiolic at 10(-4) to 10(-5). A metalloproteinase, MMP-7-ase, was inhibited by tetrahydrocannabidiolic acid, 3,7,8-trihydroxy-CPZ, acridine orange but other tissue proteinases, ATN-ase and cathepsin B, were less sensitive to these compounds. (ATN-ase is an acetyltyrosine-p-nitroanilide splitting enzyme, a serine protease). The chelate complex forming ability and electron donor capacity of the compounds may play a role in the biological effects tested. It is assumed that compounds which do not displace bivalent cations in membranes may exert an inhibitory effect on AChE, and that metalloproteinase enzymes may be promising for the treatment of degenerative brain diseases.

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