Methyl Analogues of the Experimental Alzheimer Drug Phenserine:  Synthesis and Structure/Activity Relationships for Acetyl- and Butyrylcholinesterase Inhibitory Action

Abstract

With the goal of developing potential Alzheimer's pharmacotherapeutics, we have synthesized a series of novel analogues of the potent anticholinesterases phenserine (2) and physostigmine (1). These derivatives contain methyl (3, 4, 6), dimethyl (5, 7, 8, 10, 11) and trimethyl (14) substituents in each position of the phenyl group of the phenylcarbamoyl moieties, and with N-methyl and 6-methyl substituents (12, 13, 31, 33). We also quantified the inhibitory action of these compounds against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). An analysis of the structure/anticholinesterase activity relationship of the described compounds, together with molecular modeling, confirmed the catalytic triad mechanism of the binding of this class of carabamate analogues within AChE and BChE and defined structural requirements for their differential inhibition.

The Kinetics of Inhibition of Human Acetylcholinesterase and Butyrylcholinesterase by Two Series of Novel Carbamates

“…The lack of a significant difference in k i between the enantiomers of the N-methyl,N-ethyl carbamate derivative of the AI series led us to conclude that the configuration of the chiral carbon in the rigid cyclopentyl moiety of aminoindan is not important for inhibition of rhAChE by the AI derivative, but chirality does influence inhibition by rivastigmine both of rhAChE (Bar-On et al, 2002) and hBChE, as shown previously by others (Yu et al, 2001;Luo et al, 2006).…”

“…Most published analyses of structure-activity relationships of carbamates designed as potential drugs for the treatment of AD are based on measurements of IC 50 (Yu et al, 2001;Sterling et al, 2002;Bolognesi et al, 2004;Luo et al, 2005Luo et al, , 2006Bartolucci et al, 2006). However, this parameter lacks information on the individual rate constants that govern the approach to, and the steady-state level of, enzyme activity and the rate of release of a leaving group designed to exert independent biological activity.…”

Preclinical Investigation of the Topical Administration of Phenserine: Transdermal Flux, Cholinesterase Inhibition, and Cognitive Efficacy

“…Initial in vitro studies indicated the suitability of PS for transdermal application, as would be predicted from its physicochemical characteristics (Ozawa et al, 1988;Yu et al, 2001).…”

Stereoselective inhibition of butyrylcholinesterase by enantiomers ofexo- andendo-2-norbornyl-N-n-butylcarbamates

“…The additional demonstration that central BChE rather than AChE inhibition is the best correlate of cognitive improvement in AD clinical studies with the dual cholinesterase inhibitor rivastigmine ( Figure 2) further suggests that BChE represents an intriguing target to develop drugs for the treatment of neurodegenerative disease [19][20][21] . The derivatives of physostigmine ( Figure 2) are also potential drugs for the treatment of AD 22,23 . Since rivastigmine 24 , bambuterol 25 , and physostigmine are carbamates, inhibition mechanisms of both AChE and BChE by carbamates may play important roles for the treatment of AD [19][20][21][22][23][24][25][26][27] .…”

“…The derivatives of physostigmine ( Figure 2) are also potential drugs for the treatment of AD 22,23 . Since rivastigmine 24 , bambuterol 25 , and physostigmine are carbamates, inhibition mechanisms of both AChE and BChE by carbamates may play important roles for the treatment of AD [19][20][21][22][23][24][25][26][27] . Carbaryl (1-naphthyl N-methylcarbamate, Sevin) (Figure 2), carbofuran (Furadan), propoxur (Baygon), and aldicarb (Temik) are carbamate pesticides that have activities against a broad range of insects and low mammalian toxicity 28 .…”