(Compound 4 Darvesh et al. 2008) Ki BCHE 18 micro M (for comparison Donepezil 2.21 for BCHE and 0.024 for ACHE), Ka ACHE 1800 M-1min-1 (for comparison rivastigmine 1130 M-1min-1)
Most carbamates are pseudoirreversible inhibitors of cholinesterases. Phenothiazine carbamates exhibit this inhibition of acetylcholinesterase but produce reversible inhibition of butyrylcholinesterase, suggesting that they do not form a covalent bond with the catalytic serine. This atypical inhibition is attributable to pi-pi interaction of the phenothiazine moiety with F329 and Y332 in butyrylcholinesterase. These residues are in a helical segment, referred to here as the E-helix because it contains E325 of the catalytic triad. The involvement of the E-helix in phenothiazine carbamate reversible inhibition of butyrylcholinesterase is confirmed using mutants of this enzyme at A328, F329, or Y332 that show typical pseudoirreversible inhibition. Thus, in addition to various domains of the butyrylcholinesterase active site gorge, such as the peripheral anionic site and the pi-cationic site of the Omega-loop, the E-helix represents a domain that could be exploited for development of specific inhibitors to treat dementias.
Title: Heterocyclic free radicals. Part 8. The influence of the structure and the conformation of the side-chain on the properties of phenothiazine cation-radicals substituted at nitrogen Clarke D, Gilbert BC, Hanson P, Kirk CM Ref: J Chem Soc Perkin 2, :1103, 1978 : PubMed
n 10-substituted phenothiazine cation-radicals the extent of variation in nitrogen hyperfine splitting is greatest for purely hydrocarbon substituents and is reduced on introduction of polar functions into the alkyl group. It is concluded that the substituent effect is mainly a through-bond inductive effect of the classical kind. Substituents greater than methyl show strong preferences for particular conformations about the N-C bond. Variations in the ratio a(N) : a(3-H) are interpreted in terms of changes in the fold angle of the radicals occurring in response to changes of substituent type. Chiral substituents, as found in certain phenothiazine drugs, have characteristic effects on the e.s.r. spectra of the derived cation-radicals: two non-equivalent proton splittings arise from the Beta-CH2 group.
