Cholinesterase studies with (R) (+)- and (S)(-)-5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate.
A limited number of carbamates have been found useful for treatment of cholinergic symptoms with pyridostigmine and physostigmine being the main focus. In recent years 5-(1,3,3-trimethylindolinyl)N,N-dimethylcarbamate (I) has received considerable attention in the Chinese literature for a similar role. We report on the first synthesis of stereoisomers of an analog of (I). The isomers prepared were (R)(+)-5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate (II) and (S)(-)-5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate (III). The pKa value for each isomer was 6.8. Eel acetylcholinesterase inhibition studies were carried out at 25.0 degrees C over the pH range of 6.0 to 9.0. They reflect the first pH profiles using enantiomorphs of a cholinesterase inhibitor. The inhibition potencies for (II) and (III) over the range examined were similar. At pH 7.60 the ki for II = 7.38 x 10(3) M-1 min-1 (SD = 398) and for (III) the ki = 6.67 x 10(3) M-1 min-1 (SD = 355). In accord with the findings of Wilson and Bergmann20 on physostigmine our results indicate that the protonated form of (II) and (III) is the more potent inhibitor.
Lieske
C N
CN
US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010.
Gepp
R T
RT
Maxwell
D M
DM
Clark
J H
JH
Broomfield
C A
CA
Blumbergs
P
P
Tseng
C C
CC
D000110:Acetylcholinesterase / Q000187:drug effects*; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D004524:Eels; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D007211:Indoles; C034763:cui xing ning; C082711:5-(1,3,3-trimethylindolinyl)-N-(1-phenylethyl)carbamate; D000110:Acetylcholinesterase