Tricyclic Compounds as Selective Muscarinic Antagonists: Structure Activity Relationships and Therapeutic Implications
1992; Elsevier BV; Linguagem: Inglês
10.1016/b978-0-444-88931-7.50019-0
ISSN2212-0637
AutoresWolfgang Eberlein, W. Engel, Kai M. Hasselbach, N. Michael Mayer, Gerhard Mihm, K Rudolf, Henri Doods,
Tópico(s)Ion channel regulation and function
ResumoPirenzepine, the first M1 selective receptor blocker, exhibits the following selectivity profile: The discovery of this compound, which is currently used in ulcer therapy, gave the impetus for a research project directed towards the development of selective muscarinic antagonists. The availability of muscarinic antagonists with different subtype selectivity offers opportunities for novel therapies. The target profilehas been hypothesized to be suited for the treatment of chronic obstructive airway diseases. We were successful in synthesizing compounds displaying the desired selectivity profile. Compound AQ-RA 721 has been selected for detailed pharmacological investigations. Compounds with high affinity to cardiac muscarinic receptors might be useful for the treatment of diseases associated with bradycardic disorders. The first compound of this type, AF-DX 116, has the following selectivity profile: Among the follow-up compounds the most attractive M2 antagonist is compound AQ-RA 741 which exhibits a tenfold higher activity and improved selectivity as compared to AF-DX 116. Experimental support has accumulated in recent years that selective muscarinic antagonists might exhibit interesting effects on certain functions of the CNS thus leading to new strategies of treating certain symptoms of Alzheimer's disease. Correlation of biological data with the results of rigorous conformational analyses led to the identification of “biologically active conformations” corresponding to the selectivity profiles mentioned above.
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