402475-33-6

Usage

Uses

Used in Pharmaceutical Industry:
DIMETHYL-W84 DIBROMIDE is used as a potent allosteric modulator for muscarinic receptors, specifically targeting M2-receptors. Its high selectivity and potency make it a valuable tool in the development of new drugs and therapies that aim to modulate the activity of these receptors.
Used in Medical Research:
DIMETHYL-W84 DIBROMIDE is used as a research compound to study the function and role of M2 muscarinic acetylcholine receptors in various physiological and pathological processes. This understanding can lead to the development of targeted treatments for conditions related to the dysregulation of these receptors.
Used in Drug Development:
DIMETHYL-W84 DIBROMIDE is used as a lead compound in the development of new drugs that can selectively modulate M2-receptors. This selective targeting can potentially result in more effective and safer medications with fewer side effects compared to non-selective agents.

Upstream product

• 629-03-8 1 ,6-dibromohexane 
• 579439-30-8 4-methyl-N-[3-(N,N-dimethylamino)propyl]phthalimide 
• 109-55-7 1-amino-3-(dimethylamino)propane 
• 19438-61-0 4-methylphthalic anhydride 

Relevant academic research and scientific papers

Identification of a [3H]ligand for the common allosteric site of muscarinic acetylcholine M2 receptors

Muscarinic acetylcholine receptors bind allosteric modulators at a site apart from the orthosteric site used by conventional ligands. We tested in cardiac tissue whether modulator binding to ligand-occupied muscarinic M2 receptors is a preferential event that can be detected using a radioactive allosteric agent. The newly synthesized dimethyl-W84 (N,N'-bis[3-(1,3- dihydro-1,3-dioxo-4,methyl-2H-isoindol-2-yl)propyl]-N,N,N',N'-tetramethyl- 1,6-hexanediaminium diiodide) has a particular high potency at M2 receptors occupied by the conventional antagonist N-methylscopolamine (NMS); dissociation of [3H]NMS is half-maximally retarded at an EC(50,diss) value of 3 nM. Using obidoxime as an 'allosteric antagonist,' evidence was found that dimethyl-W84 interacts with the postulated common allosteric site. Binding of [3H]dimethyl-W84 (0.3 mM; specific activity, 168 Ci/mmol) was measured in porcine heart homogenates (4 mM Na2HPO4, 1 mM KH2PO4, pH 7.4, 23°) in the presence of 1 μM NMS. Homologous competition experiments revealed two components of saturable radioligand binding: one with a high affinity (K(D) = 2 nM) and small capacity (?30% of total saturable binding) and the other with a 20,000-fold lower affinity. The B(max) value of the high affinity sites (68 fmol/mg protein) matched muscarinic receptor density as determined by [3H]NMS (79 fmol/mg). Prototype allosteric agents, alcuronium, W84 (the parent compound of the radioligand), and gallamine, displaced high affinity [3H]dimethyl-W84 binding concentration-dependently (pK(i) values = 8.62, 7.83, and 6.72, respectively). The binding affinities of the modulators were in excellent correlation with their potencies to allosterically stabilize NMS/receptor complexes (EC(50,diss) = 8.40, 7.72, and 6.74, respectively). We conclude that high affinity binding of [3H]dimethyl-W84 reflects occupation of the common allosteric site of M2 receptors.

Elevation of ligand binding to muscarinic M2 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 [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.