Hexamethonium-type allosteric modulators of the muscarinic receptors bearing lateral dibenzazepine moieties.
Alkane-bisammonium compounds carrying lateral phthalimido substituents are known to have a high affinity for the allosteric binding site of the acetylcholine M2 receptor. The purpose of this study was to replace the lateral phthalimido moieties with rigid tricyclic skeletons of a large volume in order to learn more about the function of the lateral heterocycles. In addition, methyl groups were introduced into the lateral connecting chains. Allosteric inhibition of the dissociation of [3H]N-methylscopolamine from the M2 receptors in porcine cardiac homogenates served to indicate binding of the test compounds to the allosteric site. The phthalimido groups could be replaced with dibenzazepine moieties without any loss in potency. Interestingly, the additional methyl group in the lateral spacer seems to have a significant influence on the allosteric behaviour.
Li
R
R
Department of Organic Chemistry, School of Pharmaceutical Sciences, Beijing Medical University, Beijing 100083, P.R. China.
Tränkle
C
C
Mohr
K
K
Holzgrabe
U
U
D000494:Allosteric Regulation; D000818:Animals; D003984:Dibenzazepines / Q000138:chemical synthesis / Q000494:pharmacology*; D018738:Hexamethonium / Q000138:chemical synthesis / Q000494:pharmacology*; D019832:N-Methylscopolamine / Q000378:metabolism; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine
D003984:Dibenzazepines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D018738:Hexamethonium; D019832:N-Methylscopolamine