455955-77-8Relevant academic research and scientific papers
Systematic development of high affinity bis(ammonio)alkane-type allosteric enhancers of muscarinic ligand binding
Muth, Mathias,Bender, Wiebke,Scharfenstein, Olaf,Holzgrabe, Ulrike,Balatkova, Edith,Tr?nkle, Christian,Mohr, Klaus
, p. 1031 - 1040 (2003)
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 M2 receptors using [3H]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.
A fast and efficient track to allosteric modulators of muscarinic receptors: Microwave-assisted syntheses
Schmitz, Jens,Heller, Eberhard,Holzgrabe, Ulrike
, p. 171 - 174 (2008/02/01)
By using microwave irradiation bisammonium-and bispyridinium-type allosteric modulators of muscarinic receptors can be obtained fast and efficiently.
Elevation of ligand binding to muscarinic M2 acetylcholine receptors by bis(ammonio)alkane-type allosteric modulators
Raasch, Alexandra,Scharfenstein, Olaf,Tr?nkle, Christian,Holzgrabe, Ulrike,Mohr, Klaus
, p. 3809 - 3812 (2007/10/03)
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 [3H]N-methylscopolamine ([3H]NMS) from porcine heart M2 receptors. [3H]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.
