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HERO ID
6574372
Reference Type
Journal Article
Title
1-substituted-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-alkyloximes as novel orally active and long-lasting muscarinic cholinergic agonists
Author(s)
Toja, E; Bonetti, C; Butti, A; Hunt, P; Fortin, M; Barzaghi, F; Formento, ML; Maggioni, A; Nencioni, A; Galliani, G
Year
1992
Is Peer Reviewed?
Yes
Journal
European Journal of Medicinal Chemistry
ISSN:
0223-5234
EISSN:
1768-3254
Volume
27
Issue
5
Page Numbers
519-526
Language
English
DOI
10.1016/0223-5234(92)90186-5
Web of Science Id
WOS:A1992JP95400010
Abstract
Our previous attempts to design muscarinic agonists related to arecoline with the prerequisites for clinical use were successful with the discovery of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, RU 35963, and structurally related compounds, in which the metabolically labile ester group of arecoline was replaced with the bioisosteric and stable aldoxime group. With the aim of obtaining compounds with improved cholinomimetic properties, several aryl- and alkyl-carbamates of RU 35963, as well as O-alkyl-, and O-aryl-carbamates of the 1-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, 24, have been synthesized and evaluated biologically. The most interesting molecules to emerge from the primary screening have been evaluated more extensively and their cholinomimetic profiles compared with those of the parent molecules. In vitro studies indicate that none of these prodrugs have affinity for muscarinic receptor sites and some of them (aryl-carbamates) have cholinesterase inhibiting properties. Results from in vivo experiments in mice and rats showed that these new substances, 1-[4-chlorophenyl] oxycarbonyl-1,2,5,6-tetrahydropyridine-3- carboxaldehyde-O-methyloxime (16 = RU 47213) in particular, have cholinomimetic properties that compare favourably with those of the parent compounds. After oral administration 16 was clearly superior to RU 35963 in terms of central selectivity, duration of action and therapeutic indexes.
Keywords
tetrahydropyridine aldoxime; prodrug
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