Abstract
Pirenzepine (2) is one of the most selective muscarinic M(1) versus M(2) receptor antagonists known. A series of 2 analogs, in which the piperazyl moiety was replaced by a cis- and trans-cyclohexane-1,2-diamine (3-6) or a trans- and cis-perhydroquinoxaline rings (7 and 8) were prepared, with the aim to investigate the role of the piperazine ring of 2 in the interaction with the muscarinic receptors. The structural change leading to compounds 3-6 abolished in binding assays the muscarinic M(1)/M(2) selectivity of 2, due to an increased M(2) affinity. Rather, compounds 3-6 displayed a reversed selectivity showing more affinity at the muscarinic M(2) receptor than at all the other subtypes tested.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CHO Cells
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Cricetinae
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Cricetulus
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Cyclohexylamines / chemistry*
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Gene Expression Regulation
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Guinea Pigs
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Heart Atria / drug effects
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Humans
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Male
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Models, Molecular
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Molecular Structure
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Muscarinic Antagonists / chemistry*
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Muscarinic Antagonists / pharmacology*
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Muscle, Skeletal / metabolism
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Pirenzepine / analogs & derivatives*
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Pirenzepine / chemistry*
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Pirenzepine / pharmacology
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Protein Binding
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Quinoxalines / chemistry*
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Rabbits
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Receptors, Muscarinic / metabolism
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Structure-Activity Relationship
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Vas Deferens / drug effects
Substances
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Cyclohexylamines
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Muscarinic Antagonists
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Quinoxalines
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Receptors, Muscarinic
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Pirenzepine
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1,2-cyclohexanediamine