Systematic development of high affinity bis(ammonio)alkane-type allosteric enhancers of muscarinic ligand binding.
Bis(ammonio)alkane compounds carrying lateral phthalimidopropyl substituents on the nitrogen atoms belong to the archetypal muscarinic allosteric agents. Herein, a series of symmetrical and nonsymmetrical compounds was synthesized in which the phthalimide residues were replaced by differently substituted imide moieties. The allosteric action was measured in porcine heart muscarinic M(2) receptors using [(3)H]N-methylscopolamine (NMS) as a ligand for the orthosteric receptor site in equilibrium binding and dissociation experiments. 1,8-Naphthalimido residues conferred an up to 100-fold gain in affinity leading into the low nanomolar range, while the inhibition of NMS binding was maintained. Additional propyl chain methylation was accompanied by an allosteric elevation of orthosteric ligand binding. In general, the gain in allosteric activity achieved by ring variation plus propyl chain methylation on one side of the molecule could not be augmented by symmetrical variations. The elevation of the ligand binding can be explained by different quantitative structure-activity relationships for the affinities to the free and the orthoster-liganded receptor.
Muth
Mathias
M
Institute of Pharmacy and Food Chemistry, University of Würzburg, Am Hubland, D-97074 Würzburg, Federal Republic of Germany.
Bender
Wiebke
W
Scharfenstein
Olaf
O
Holzgrabe
Ulrike
U
Balatkova
Edith
E
Tränkle
Christian
C
Mohr
Klaus
K
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D066298:In Vitro Techniques; D008024:Ligands; D009206:Myocardium / Q000378:metabolism; D010795:Phthalic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012044:Regression Analysis; D013552:Swine
D000473:Alkanes; D008024:Ligands; D010795:Phthalic Acids; D000644:Quaternary Ammonium Compounds; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic