AMINOPYRIDINE CARBAMIC ACID-ESTERS - SYNTHESIS AND POTENTIAL AS ACETYLCHOLINESTERASE INHIBITORS AND ACETYLCHOLINE RELEASERS

4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed go...

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Published inJournal of pharmaceutical sciences Vol. 81; no. 4; pp. 380 - 385
Main Authors SHUTSKE, GM, TOMER, JD, KAPPLES, KJ, HRIB, NJ, JURCAK, JG, BORES, GM, HUGER, FP, PETKO, W, SMITH, CP
Format Journal Article
LanguageEnglish
Published WASHINGTON AMER PHARMACEUTICAL ASSN 01.04.1992
Subjects
Acetylcholine - metabolism
Aminopyridines - chemical synthesis
Aminopyridines - pharmacology
Animals
Carbamates - chemical synthesis
Carbamates - pharmacology
Chemistry
Chemistry, Medicinal
Chemistry, Multidisciplinary
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - pharmacology
Corpus Striatum - drug effects
Corpus Striatum - metabolism
Life Sciences & Biomedicine
Male
Pharmacology & Pharmacy
Physical Sciences
Rats
Rats, Inbred Strains
Science & Technology
CORTEX
SLICES
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Summary:4-Amino-3-pyridyl carbamates (2a-c) were synthesized as potential acetylcholinesterase inhibitors and acetylcholine releasers on the basis of the reported activity of the analogous N-(4-amino-3-pyridyl)-N',N'-dimethylurea (1). Although 4-amino-3-pyridyl N,N-dimethylcarbamate (2b) showed good cholinesterase inhibition [concentration that elicited a 50% reduction in the maximal enzyme response (IC50) was 13.4-mu-M], it had no effect on the stimulated release of [H-3]acetylcholine from rat striatal slices. 4-[[(Dimethylamino)methylene]amino]-3-pyridyl N,N-dimethylcarbamate (7a), an intermediate in the synthesis of 2b, demonstrated surprisingly good cholinesterase inhibition (IC50 was 9.4-mu-M) but showed no activity as a releaser. A precursor to 7a, N-(3-hydroxy-4-pyridyl)-N',N'-dimethylformamidine (6a), showed some activity in release but was not an esterase inhibitor, whereas the precursor to 6a, 4-amino-3-pyridinol (5a), was a potent releaser. A new synthesis of 5a, based on an ortho-directed lithiation strategy, is also reported.
ISSN:0022-3549
DOI:10.1002/jps.2600810419