Source:http://linkedlifedata.com/resource/pubmed/id/12747793
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
11
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pubmed:dateCreated |
2003-5-15
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pubmed:abstractText |
Expedient syntheses of C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones are reported to begin with 2,5-disubstituted pyridines. Catalytic reduction of the pyridine to the piperidine followed by treatment with ethyl acrylate and Dieckmann cyclization gave diastereomeric mixtures of C(8) substituted 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes, which were separable by chromatography. We found that the catalytic reduction (PtO2, H2) procedure provided the cis-substituted piperidine but that pyridine reduction was accompanied by competitive cleavage of the C(2) pyridyl substituent. Accordingly, an alternative route was devised that afforded a diastereomeric mixture of the cis- and trans-2,5-disubstituted piperidine. Treatment of the substituted pyridine with m-CPBA gave the pyridine N-oxide, which was reduced to the piperidine by sequential reduction with ammonium formate in the presence of Pd-C followed by NaBH3CN. Addition of ethyl acrylate completed the synthesis of the substituted piperidine. The overall four-step reaction gave higher yields (57%) than the two-step procedure (13%) with little cleavage of the C(2) pyridyl substituent. Acid decarboxylation of the bicyclo[3.3.1]non-3-enes provided the C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones. Structural studies revealed diagnostic 13C NMR signals that permit assignment of the orientation of the C(8) substituent. Pharmacological investigations documented that 3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-enes efficiently bind to the human M1-M5 muscarinic receptors and function as antagonists. We observed that exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (3) displayed the highest affinity, exhibiting Ki values at all five muscarinic receptors that were approximately 10-50 times lower than carbachol and approximately 30-230 times lower than arecoline. Receptor selectivity was observed for 3. Compound 3 contained two different pharmacophores found in many muscarinic receptor ligands, and preliminary findings indicated the importance of both structural elements for maximal activity. Compound 3 serves as a novel lead compound for further drug development.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
22
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2216-26
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:12747793-Animals,
pubmed-meshheading:12747793-Bicyclo Compounds, Heterocyclic,
pubmed-meshheading:12747793-Binding, Competitive,
pubmed-meshheading:12747793-Cell Line,
pubmed-meshheading:12747793-Crystallography, X-Ray,
pubmed-meshheading:12747793-Humans,
pubmed-meshheading:12747793-Inositol Phosphates,
pubmed-meshheading:12747793-Magnetic Resonance Spectroscopy,
pubmed-meshheading:12747793-Membranes,
pubmed-meshheading:12747793-Muscarinic Antagonists,
pubmed-meshheading:12747793-Radioligand Assay,
pubmed-meshheading:12747793-Stereoisomerism,
pubmed-meshheading:12747793-Structure-Activity Relationship
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pubmed:year |
2003
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pubmed:articleTitle |
C(8) substituted 1-azabicyclo[3.3.1]non-3-enes and C(8) substituted 1-azabicyclo[3.3.1]nonan-4-ones: novel muscarinic receptor antagonists.
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pubmed:affiliation |
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7360, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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