SELECTIVE BUTYRYLCHOLINESTERASE INHIBITORS AMONG DIALKYLPHOSPHORAMIDOFLUORIDATES

Abstract

Supposition of a relationship between blood butyrylcholinesterase (BuChE) activity and its lipid composition was reported in a number of works [1–7]. To check this hypothesis, a search of selective BuChE inhibitors among substituted cyclohexyl ester N,N-dialkylphosphoramidofluoridic acids has been accomplished by us. For synthesis of substances to be investigated, interaction of N,N- dialkylphosphoramidic difluorides with Na and Al derivatives of corresponding alcohols was used. Investigation of purified, water soluble preparations of BuChE and acetylcholinesterase (AChE) indicated that there were high selective BuChE inhibitors among the investigated compounds. In particular, for N,N-diethyl-O-(trans-2-piperidinocyclohexyl)phosphoramidofluoridate, the reaction constants for cholinesterase inhibition were: k⁰ _BuChE = 1,4 × 10⁸ M⁻¹ × min⁻¹, k⁰ _AChE = 2,1 × 10⁴ M⁻¹ × min⁻¹ and for its derivative, 1-(trans-2-N,N-diethylamidofluorophosphoryloxycyclohexyl)-1-methylpiperidinium iodide k⁰ _BuChE = 2,6 × 10⁷ M⁻¹ × min⁻¹, while the AChE inhibition by that compound was reversible (K_i = 9.8 × 10⁻⁶ M).

Key Words:

• Acetylcholinesterase: butyrylcholinesterase
• O-alkyl-N,N-dialkylphosphoramidofluoridates: inhibitor