Elevation of ligand binding to muscarinic M(2) acetylcholine receptors by bis(ammonio)alkane-type allosteric modulators.

Bis(ammonio)alkane-type compounds are archetypal muscarinic allosteric modulators. Phthalimido-substituted hexane-bis-ammonium agents were methylated in the phthalimide moieties and the lateral propyl side chains. All compounds retarded allosterically the dissociation of the orthosteric ligand [(3)H]N-methylscopolamine ([(3)H]NMS) from porcine heart M(2) receptors. [(3)H]NMS equilibrium binding was reduced, left unaltered, or elevated, depending on the degree and position of methylation. This is the first time that an allosteric elevation of ligand binding is demonstrated for bis(ammonio)alkane-type compounds.

[1]  U. Holzgrabe,et al.  N+/Si replacement as a tool for probing the pharmacophore of allosteric modulators of muscarinic M2 receptors: Synthesis, allosteric potency, and positive cooperativity of silicon-based W84 derivatives , 2002 .

[2]  U. Holzgrabe,et al.  Structure-activity relationships in a series of bisquaternary bisphthalimidine derivatives modulating the muscarinic M(2)-receptor allosterically. , 2000, Journal of medicinal chemistry.

[3]  U. Holzgrabe,et al.  Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors. , 2000, Life sciences.

[4]  U. Holzgrabe,et al.  Bisquaternary ligands of the common allosteric site of M2 acetylcholine receptors: search for the minimum essential distances between the pharmacophoric elements. , 1999, Journal of medicinal chemistry.

[5]  A. Christopoulos.  Assessing the distribution of parameters in models of ligand-receptor interaction: to log or not to log. , 1998, Trends in pharmacological sciences.

[6]  K. Mohr,et al.  M2 receptor binding of the selective antagonist AF-DX 384: possible involvement of the common allosteric site. , 1998, Molecular pharmacology.

[7]  E. Kostenis,et al.  Two-point kinetic experiments to quantify allosteric effects on radioligand dissociation. , 1996, Trends in pharmacological sciences.

[8]  S. Lazareno,et al.  Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors: interactions of strychnine and acetylcholine at muscarinic receptors. , 1995, Molecular pharmacology.

[9]  J. Proska,et al.  Mechanisms of steric and cooperative actions of alcuronium on cardiac muscarinic acetylcholine receptors. , 1994, Molecular pharmacology.

[10]  E. El-Fakahany,et al.  Influence of ligand choice on the apparent binding profile of gallamine to cardiac muscarinic receptors. Identification of three main types of gallamine-muscarinic receptor interactions. , 1988, The Journal of pharmacology and experimental therapeutics.

[11]  F. Ehlert,et al.  Estimation of the affinities of allosteric ligands using radioligand binding and pharmacological null methods. , 1988, Molecular pharmacology.