| Popis: |
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. |
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