Abstract
Several novel methoctramine-related tetraamines were designed, and their biological profiles at muscarinic receptor subtypes were assessed by functional experiments in isolated guinea pig and rat atria (M2) and smooth muscle (ileum and trachea, M3) and by binding assays in rat cortex (M1), heart (M2), and submaxillary gland (M3) homogenates and NG 108-15 cells (M4). Tripitramine, a nonsymmetrical tetraamine, resulted in the most potent and the most selective muscarinic M2 receptor antagonist of the series (pA2 = 9.14-9.85; pKi = 9.54). Spirotramine (FC 15-94), a symmetrical tetraamine, was able to differentiate between muscarinic M1 receptors (pKi = 7.88) and the other subtypes (M2, pKi = 6.20; M3, pKi = 5.81; M4, pKi = 6.27). Thus, tripitramine and spirotramine could be valuable tools for the pharmacological classification and characterization of muscarinic receptor subtypes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Atrial Function
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Benzodiazepines / pharmacology
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Benzodiazepinones / pharmacology
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Diamines / chemistry
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Diamines / pharmacology*
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Drug Design
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Guinea Pigs
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Heart Atria / drug effects
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Ileum / drug effects
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Ileum / physiology
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Muscarinic Antagonists / chemistry
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Muscarinic Antagonists / pharmacology*
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Muscle Contraction / drug effects
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Muscle Contraction / physiology
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Muscle, Smooth / drug effects
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Muscle, Smooth / physiology
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Parasympatholytics / chemistry
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Parasympatholytics / pharmacology*
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Piperidines / pharmacology
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Pirenzepine / pharmacology
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Rats
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Receptors, Muscarinic / classification
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Receptors, Muscarinic / metabolism*
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Structure-Activity Relationship
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Submandibular Gland / drug effects
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Submandibular Gland / metabolism
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Trachea / drug effects
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Trachea / metabolism
Substances
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Benzodiazepinones
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Diamines
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Muscarinic Antagonists
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Parasympatholytics
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Piperidines
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Receptors, Muscarinic
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AQ-RA 741
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Benzodiazepines
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tripitramine
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Pirenzepine
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methoctramine