- Design, synthesis, and action of oxotremorine-related hybrid-type allosteric modulators of muscarinic acetylcholine receptors
-
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.
- Disingrini, Teresa,Muth, Mathias,Dallanoce, Clelia,Barocelli, Elisabetta,Bertoni, Simona,Kellershohn, Kerstin,Mohr, Klaus,De Amici, Marco,Holzgrabe, Ulrike
-
-
Read Online
- Polyamines. Part II: Spectroscopic properties of N,N-dimethyl-3-phthalimidopropylammonium acetate and hydrochloride and supramolecular interactions in their crystals
-
N,N-Dimethyl-3-phthalimidopropylammonium acetate and hydrochloride have been characterized by X-ray diffraction, FT-IR, Raman and NMR spectroscopy. Also B3LYP and DFT calculations have been carried out. The optimized bond lengths, bond angles and torsion angles calculated by B3LYP/6-31G(d,p) approach have been compared with the X-ray data. The screening constants for 13C and 1H atoms have been calculated by the GIAO/B3LYP/6-31G(d,p) approach and analyzed. Linear correlations between the experimental 1H and 13C chemical shifts and the computed screening constants confirm the optimized geometry. The packing of the both molecules is dominated by hydrogen bonds, including the weak C{single bond}H?O bonds. The supramolecular structure is organized into hydrophilic and hydrophobic segments.
- Borowiak, Teresa,Wolska, Irena,Jensz, Piotr,Kowalczyk, Iwona,Brycki, Bogumi?,Sztul, Adrianna
-
-
Read Online
- Allosteric effect on muscarinic M2-receptors of derivatives of the alkane-bis-ammonium compound W84. Comparison with bispyridinium-type allosteric modulators
-
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
- Kostenis, E.,Holzgrabe, U.,Mohr, K.
-
-
Read Online
- Study of N,N-dimethyl(carboethoxymethyl)-3-phthalimidopropylammonium chloride dihydrate by DFT calculations, NMR and FTIR spectroscopy
-
N,N-dimethyl(carboethoxymethyl)-3-phthalimidopropylammonium chloride dihydrate (1) and N,N-dimethyl(carboxymethyl)-3-phthalimidopropylammonium hydrochloride (3) have been obtained in reaction of N,N-dimethyl-3-phthalimidopropylamine with ethyl chloroacetate and chloroacetic acid, respectively. N,N-dimethyl(carboethoxymethyl)-3-phthalimido-propylammonium chloride dihydrate (1) has been characterized by FTIR and NMR spectroscopy. Moreover, for (1) and (3) B3LYP calculations have been carried out. The optimized bond lengths, bond angles and torsion angles calculated by B3LYP/6-31G(d,p) approach have been presented. Both FTIR and Raman spectra of (1) are consistent with the calculated structures in the gas phase. Correlations between the experimental 1H and 13C NMR chemical shifts (δexp) of investigated compound in D2O, and the GIAO/B3LYP/6-31G(d,p) calculated magnetic isotropic shielding tensors (σcalc), δexp = a + b σcalc, are reported. The assignments of the anharmonic experimental solid state vibrational frequencies of (1) based on the calculated B3LYP/6-31G(d,p) harmonic frequencies have been made. Linear correlations between the experimental 1H and 13C chemical shifts and the computed screening constants confirm the optimized geometry.
- Kowalczyk, Iwona
-
-
Read Online
- Dualsteric muscarinic antagonists-orthosteric binding pose controls allosteric subtype selectivity
-
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.
- Schmitz, Jens,Van Der Mey, Dorina,Bermudez, Marcel,Kl?ckner, Jessica,Schrage, Ramona,Kostenis, Evi,Tr?nkle, Christian,Wolber, Gerhard,Mohr, Klaus,Holzgrabe, Ulrike
-
-
Read Online
- A fast and efficient track to allosteric modulators of muscarinic receptors: Microwave-assisted syntheses
-
By using microwave irradiation bisammonium-and bispyridinium-type allosteric modulators of muscarinic receptors can be obtained fast and efficiently.
- Schmitz, Jens,Heller, Eberhard,Holzgrabe, Ulrike
-
-
Read Online
- Antitrypanosomal activity of quaternary naphthalimide derivatives
-
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.
- Muth, Mathias,Hoerr, Verena,Glaser, Melanie,Ponte-Sucre, Alicia,Moll, Heidrun,Stich, August,Holzgrabe, Ulrike
-
-
Read Online
- 3-(1,3-Dioxoisoindolin-2-yl)-N,N-dimethylpropan-1-ammonium perchlorate: Synthesis, crystal structure, docking study and in vitro anticancer activity against the human hepatomas cell line (Hep G2)
-
2-(3-(Dimethylamino)propyl)isoindoline-1,3?dione (DAPID) has been synthesized and utilized to produce 3-(1,3-dioxoisoindolin-2-yl)-N,N-dimethyl propan-1-ammonium perchlorate (DIDAP). Both DAPID and DIDAP were characterized using different spectroscopic techniques. Structure of the DIDAP has been determined using single crystal X-ray diffraction technique. DIDAP found to self assemble in a helical motif in its supramolecular structure with the aid of different hydrogen bonding, Cg???Cg and short interatomic contacts in the solid state. Shape index and Curvedness surfaces indicated p-stacking with different features in opposed sides of the molecule. Fingerprint plot showed C???C contacts with similar contributions to the crystal packing in comparison with those associated to hydrogen bonds. Enrichment ratios for H???H, O???H and C???C contacts revealed a high propensity to form in the crystal. The compound DIDAP exhibited anticancer activity against the human hepatomas cell line (Hep G2). The molecular docking study also supports the anticancer activity of the title compound.
- Das, Purak,Das, Rajesh Kumar,Kumar, Pranesh,Mukherjee, Deboshmita,Reja, Sahin
-
-
- 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 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.
- Muth, Mathias,Bender, Wiebke,Scharfenstein, Olaf,Holzgrabe, Ulrike,Balatkova, Edith,Tr?nkle, Christian,Mohr, Klaus
-
p. 1031 - 1040
(2007/10/03)
-
- Cyanine dyes
-
A cyanine dye having the structure has an overall positive charge greater than ±1, by virtue of the presence of one to five positively charged N or P or S atoms, and also has a reactive or functional group by which it may be linked to a biomolecule or a solid surface.
- -
-
-