Date of Award


Degree Type


Degree Name

Doctor of Pharmacy (PharmD)


As part of a study to investigate metal chelates as possible inhibitors of acetylcholinesterase, copper chelates of 1 ,3 diaminopropanol-2, 1, 3 diaminopropane, and hydroxy-1-proline are examined. Since the chelate solutions contain mixtures of species in equilibrium, it is necessary to calculate the concentrations of pertinent species under experimental conditions. Equations are derived which can be used to calculate the concentrations of individual species in an equilibrium mixture of ligand and copper under fixed conditions of concentration and pH with the aid of an IBM 1410 computer. Initial measurements of reaction velocity of enzyme-substrate breakdown to enzyme plus acid products, are made by observing the speed of pH drop with the aid of a Beckman Automatic Titrator. Selection of equilibrium pH values and ligand-metal ratios is dependent on the formation constants calculated for each system. Enzyme kinetic studies are used in an effort to determine the nature of the inhibition of acetylcholinesterase. It is found that (a) 1-1 ligand-copper chelate inhibit the acetylcholinesterase system, (b) free cupric ion may inhibit the enzyme system if concentrations greater than 1 x 10-6M are present in the equilibrium mixture, (c) coordination vacancies on the metal ion are necessary prerequisites for inhibition, (d) 1-1 ligandcopper chelates of 1,3 diaminopropanol inhibit the enzyme in an essentially "competitive" manner, (e) 1-1 ligand-copper chelates of 1 ,3 diaminopropane inhibit the enzyme in an essentially "noncompetitive" manner, (f) 1-1 ligand-copper chelates of hydroxy1-proline exhibit a "yield value" (or critical concentration requirement) before any inhibition occurs, and (g) the equilibrium pH of the experiments affects both the extent and nature of the inhibition.