Cholinesterase Studies with (R)(+)- And(S)(-)-5-(L,3,3-Trimethylindolinyl)-Al(L- Phenylethyl) Carbamate

Abstract

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-(l,3,3-trimethylindolinyl)/V,/V-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-(l,3,3-trimethylindolinyl)-A^r-(l-phenylethyl(carbamate (II) and (S)(–)-5-(l,3,3-trimethylmdolinyl)-iV-(1-phenylethyl (carbamate (III). The pK_a value for each isomer was 6.8. Eel acetylcholinesterase inhibition studies were carried out at 25.0°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 k, for II = 7.38 ↣ 10³ M^_1 min⁻¹ (SD = 398) and for (III) the k_i = 6.67 ↣ 10³M^_1min^_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.

Key Words: :

• Carbamates
• stereoisomers
• acetylcholinesterase
• inhibition