13474-65-2Relevant articles and documents
Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors
Disingrini, Teresa,Muth, Mathias,Dallanoce, Clelia,Barocelli, Elisabetta,Bertoni, Simona,Kellershohn, Kerstin,Mohr, Klaus,De Amici, Marco,Holzgrabe, Ulrike
, p. 366 - 372 (2006)
A novel series of muscarinic receptor ligands of the hexamethonio-type was prepared which contained, on one side, the phthalimidopropane or 1,8-naphthalimido-2,2-dimethylpropane moiety typical for subtype selective allosteric antagonists and, on the other, the acetylenic fragment typical for the nonselective orthosteric muscarinic agonists oxotremorine, oxotremorine-M, and related muscarinic agonists. Binding experiments in M2 receptors using [3H]N-methylscopolamine as an orthosteric probe proved an allosteric action of both groups of hybrids, 7a-10a and 8b-10b. The difference in activity between a-group and b-group hybrids corresponded with the activity difference between the allosteric parent compounds. In M1-M 3 muscarinic isolated organ preparations, most of the hybrids behaved as subtype selective antagonists. [35S]GTPγS binding assays using human M2 receptors overexpressed in CHO cells revealed that a weak intrinsic efficacy was preserved in 8b-10b. Thus, attaching muscarinic allosteric antagonist moieties to orthosteric muscarinic agonists may lead to hybrid compounds in which functions of both components are mixed.
Allosteric effect on muscarinic M2-receptors of derivatives of the alkane-bis-ammonium compound W84. Comparison with bispyridinium-type allosteric modulators
Kostenis, E.,Holzgrabe, U.,Mohr, K.
, p. 947 - 954 (1994)
The symmetrically shaped W84 = N,N,N',N'-tetramethyl-N,N'-bis-(3-phthalimido-propyl)-N,N'-hexane-1,6-diyl-bisammonium dibromide is a potent allosteric stabilizer of antagonist-binding to cardiac muscarinic M2-receptors.The ability of unilaterally shortened W84 derivatives to allosterically retard the dissociation of N-methylscopolamine (NMS) from M2-receptors was determined in porcine cardiac membranes (3 mM MgHPO4, 50 mM TrisHCl, pH 7.3, 37 deg C).Shortening was accompanied by a reduction of the allosteric activity.For instance, W84 prolonged the half-lif e of NMS dissociation (control t1/2 = 2.0 min) by a factor of 2 at a concentration of EC50 = 1.3 μM, whereas a derivative unilaterally lacking phthalimidopropyldimethylammonium was 40-fold less potent.It is concluded that the whole W84 molecule interact with the allosteric site of the receptor.The structure-activity relationships found with this series of agents did not parallel findings made previously with similarly modified derivatives of the bispyridinium compound DUO 3, (E,E)-1,1'-(1,3-propanediyl)-bismethyl>pyridinium>dibromide, despite considerable similarity with respect to molecular shape and charge distribution. muscarinic receptor/ porcine myocardium/ allosteric modulation/ W84/ structure-activity relationship
Dualsteric muscarinic antagonists-orthosteric binding pose controls allosteric subtype selectivity
Schmitz, Jens,Van Der Mey, Dorina,Bermudez, Marcel,Kl?ckner, Jessica,Schrage, Ramona,Kostenis, Evi,Tr?nkle, Christian,Wolber, Gerhard,Mohr, Klaus,Holzgrabe, Ulrike
, p. 6739 - 6750 (2014)
Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal-and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure-activity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.
Antitrypanosomal activity of quaternary naphthalimide derivatives
Muth, Mathias,Hoerr, Verena,Glaser, Melanie,Ponte-Sucre, Alicia,Moll, Heidrun,Stich, August,Holzgrabe, Ulrike
, p. 1590 - 1593 (2007)
Sleeping sickness caused by Trypanosoma brucei gambiense and rhodesiense is fatal if left untreated. Due to the toxicity of drugs currently used and the emerging resistance against these drugs new lead compounds are urgently needed. Within the frame of a broad screening program for drugs with antitrypanosomal activity, some highly potent tertiary and quaternary mono- and bisnaphthalimides being active in the lower micromolar and nanomolar range of concentration have been identified. These compounds are easily available via a two- or three-step microwave-driven synthesis with high yield.
