Chemico-Biological Interactions 119 – 120 (1999) 173 – 181
3-Hydroxyquinuclidinium derivatives: synthesis of
compounds and inhibition of acetylcholinesterase
Elsa Reiner
a,
*, Mira S krinjaric ´-S poljar
a
, Sanja Dunaj
a
,
Vera Simeon-Rudolf
a
, Ines Primoz ic
b
, Srðanka Tomic ´
b
a
Institute for Medical Research and Occupational Health, Ksaerska c. 2, P.O. Box 291,
10001 Zagreb, Croatia
b
Department of Chemistry, Faculty of Science and Mathematics, Uniersity of Zagreb,
Strossmayero trg 14, 10000 Zagreb, Croatia
Abstract
Four compounds were prepared: 3-hydroxy-1-methylquinuclidinium iodide (I), 3-(N,N-
dimethylcarbamoyloxy)-1-methylquinuclidinum iodide (II), and two conjugates of I and II
with 2-hydroxyiminomethyl-3-methylimidazole in which two parts of the molecule were
linked by –CH
2
–O–CH
2 -
(III and IV). III and IV are new compounds and their synthesis
and physical data were given. All compounds were tested as inhibitors of human erythrocyte
acetylcholinesterase (EC 3.1.1.7, AChE). The enzyme activity was measured in 0.1 M
phosphate buffer (pH 7.4) at 10 and 37°C with acetylthiocholine (ATCh) as the substrate.
The obtained enzyme/inhibitor dissociation constants were between 0.05 and 0.5 mM at 10°C
and between 0.2 and 0.6 mM at 37°C. At both temperatures compounds III and IV had
higher affinities for the enzyme than compounds I and II and this difference was more
pronounced at 10 than at 37°C. The carbamates II and IV were also progressive AChE
inhibitors. For compound II the rate constants of inhibition were 6300 and 2020 M
-1
min
-1
at 37 and 10°C, respectively. Compound IV was a very weak carbamoylating agent
with rate constants of inhibition of 100 and 63 M
-1
min
-1
at 37 and 10°C, respectively. The
oxime group in compounds III and IV hydrolyzed ATCh at rates of 23 and 3.2 M
-1
min
-1
at 37 and 10°C, respectively. © 1999 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Quinuclidinium-imidazolium compounds; Quinuclidinium carbamates; Synthesis
of quinuclidinium derivatives; Reversible and progressive acetylcholinesterase inhibition;
Reaction of acetylthiocholine with quinuclidinium oximes
* Corresponding author. Tel.: +385-1-4673188; fax: +385-1-4673303.
0009-2797/99/$ - see front matter © 1999 Elsevier Science Ireland Ltd. All rights reserved.
PII:S0009-2797(99)00026-5