EFFECT OF CHARGE ON CARBAMYLATION AND BINDING CONSTANTS OF EEL ACETYLCHOLINESTERASE IN REACTION WITH NEOSTIGMINE AND RELATED CARBAMATES

The effect of charged quaternary ammonium groups on the carbamylation, k2, and binding, Ka, constants governing inhibition of eel acetylcholinesterase by neostigmine and 13 related charged and uncharged phenyl N-methyl- and phenyl N,N-dimethylcarbamates was studied. Carbamates with substituents which bound well to the anionic site, whether charged or uncharged, were characterized by relatively high rates of carbamylation. For example, the k2 values of N-methylneostigmine and of one of its carbon isosteres were 142 ± 4 and 97 ± 4 min-1 at 25°, respectively. The phenyl substituents of the N-methylcarbamates appeared to bind more strongly to the anionic site than did those of the comparable N,N-dimethyl compounds. Orientation with respect to the anionic site seemed to be the predominant factor determining rates of carbamylation. The coulombic and noncoulombic energies associated with binding of substituents to the anionic site were calculated. The Ka and k2 values of five carbamates and of diisopropyl phosphorofluoridate in reaction with eel and erythrocyte acetylcholinesterase were compared. © 1969, American Chemical Society. All rights reserved.