Abstract
Two new series of 1-(1,2,5-thiadiazol-4-yl)-4-azatricyclo[2.2.1.0(2, 6)]heptanes were synthesized and evaluated for their in vitro activity in cell lines transfected with either the human M1 or M2 receptor. 3-Phenyl-2-propyn-1-yloxy and -1-ylthio analogues substituted with halogen in the meta position showed high functional potency, efficacy, and selectivity toward the M1 receptor subtype. A quite unique functional M1 receptor selectivity was observed for compounds 8b, 8d, 8f, 9b, 9d, and 9f. Bioavailability studies in rats indicated an oral bioavailability of about 20-30%, with the N-oxide as the only detected metabolite.
MeSH terms
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Animals
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry*
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Aza Compounds / pharmacokinetics
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Aza Compounds / pharmacology
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Binding, Competitive
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Biological Availability
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CHO Cells
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Cell Line
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Cerebral Cortex / metabolism
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Cricetinae
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Cyclic AMP / biosynthesis
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Heptanes / chemical synthesis
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Heptanes / chemistry*
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Heptanes / pharmacokinetics
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Heptanes / pharmacology
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Humans
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Hydrolysis
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In Vitro Techniques
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Mice
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Muscarinic Agonists / chemical synthesis
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Muscarinic Agonists / chemistry*
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Muscarinic Agonists / pharmacokinetics
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Muscarinic Agonists / pharmacology
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Phosphatidylinositols / metabolism
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Radioligand Assay
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Rats
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Receptor, Muscarinic M1
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Receptor, Muscarinic M2
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Receptors, Muscarinic / drug effects*
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Receptors, Muscarinic / metabolism
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Structure-Activity Relationship
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Thiadiazoles / chemical synthesis
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Thiadiazoles / chemistry*
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Thiadiazoles / pharmacokinetics
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Thiadiazoles / pharmacology
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Transfection
Substances
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Aza Compounds
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Heptanes
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Muscarinic Agonists
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Phosphatidylinositols
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Receptor, Muscarinic M1
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Receptor, Muscarinic M2
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Receptors, Muscarinic
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Thiadiazoles
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Cyclic AMP