Decamethonium structure

Starting with this hypothetical structure-activity relationship, the syntheses and biological investigations of 210-215 and decamethonium iodide were carried out130,13 U As an example, the synthesis of 212 is described in Scheme 26. The pharmacological and toxicological data are given in Table 20 and Table 21, respectively. 

In this connection it shall be pointed out that some permethylated a,co-bis-(ammoniummethyl)polysiloxanes of type 216 are also very toxic, depending on the number of SiO-units132l This could possibly be explained by the structural similarity to decamethonium. 

Decamethonium (Figure 6.49) was the first synthetic curare-like muscle relaxant, but has since been superseded. In tubocurarine, the two nitrogens are also separated by ten atoms, and at physiological pHs it is likely that both centres will be positively charged. Obviously, the interatomic distance (1.4 nm in tubocurarine) is very dependent on the structure and stereochemistry rather than just the number of atoms separating the centres, but an extended conformation of decamethonium approximates to this distance. Suxamethonium... 

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

Since the aminopyridazine derivatives have a comparable size to decametho-nium and it is likely that they interact in a similar way with the binding site, we took the protein structure from the AChE-decamethonium complex for further docking. 

Fig. 11.2 Comparison between the predicted position of the aminopyridazine 3y (dark gray) and the X-ray structure of the AChE-decamethonium (gray) complex.

Figure 7.4. Superimposition ofthe investigated crystal structures of AChE in complex with huperzine (black), tacrine (dark-grey), edrophonium (grey) and decamethonium (light-grey). Only the amino acid residues close to the binding site are displayed.

Eigure 29.4 shows the predicted position of an aminopyridazine in comparison to the position of decamethonium observed in the corresponding crystal structure. The hydro-phobic parts of the aminopyridazine inhibitors interact with various aromatic residues in the binding pocket. The benzyl... 

Figure 1. Schematic of the probable physical structure of acetylcholinesterase. One physical region carries the esteratic site, which is proximal to one anionic site (Site I) the other region would carry at least four anionic sites, and would be homologous to the acetylcholine receptor of the motor end plate excitable membrane. Sites I and II are masked by DPA, but Site II can be regenerated at alkaline pH. Decamethonium (C10) would interact at least with Sites I and II whereas curare would bind at III and TV, and perhaps at II and III. Most quaternary salt substituents bind on the anionic chain [exo-binding (26, 36, 42.

Rg. 12.4 Examples of functional groups encountered in open, difunctional, polymethylenic compounds and structure of decamethonium. 

For the muscle relaxing properties of tubocurarine (D 22.1.2), for instance, only part of the complex structure of this alkaloid is necessary the presence of two quarternary iV-atoms at a certain distance from each other. This structure is mimicked in the pharmacologically similar synthetically prepared compounds of the decamethonium and suxamethonium type, in which both the quarternary A -atoms are separated either by a simple saturated carbon chain or a succinic acid-bischoline-ester residue. 

Category 2. Antibodies with recognition profiles confined to the ammonium groups but which cross-react with, and are inhibited almost equally well by, each of the NMBDs with the same or similar groups linked to the nitrogens. Examples include succinylcholine and decamethonium rf-mbocurarine and atracurium and pancuronium and vecuronium. However, since differences occur in the structures attached to the nitrogens in some NMBDs, antibodies to one NMBD, for example, succinylcholine, may not readily cross-react with, and be inhibited by, some other NMBDs, for example, rocuronium. 

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