Quaternary ammonium muscle relaxants

Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs for muscle relaxation, most commonly in anasthesia. It is necessary to prevent spontaneous movement of muscle during surgical operations. Muscle relaxants inhibit neuron transmission to muscle by blocking the nicotinic acetylcholine receptor. What they have in common and is necessary for their effect is having quaternary ammonium groups, usually two. Some of them are found in nature and others are synthesized molecules.cite journal | author = T. Raghavendra | title = Neuromuscular blocking drugs: discovery and development | year = 2002 | journal = Journal of the Royal Society of Medicine | volume = 95 | pages = 363–367 | url = http://www.jrsm.org/cgi/content/full/95/7/363 | doi = 10.1258/jrsm.95.7.363 ] cite journal | title = Neuromuscular block | author = W. C. Bowman | journal = British Journal of Pharmacology | year = 2006 | volume = 147 | pages = S277–S286 | doi = 10.1038/sj.bjp.0706404]

History

Curare is a crude extract from South American plants. It was known in the 19th century to have a paralysing effect. D-tubocurarine a "mono"-quaternary alkaloid was isolated from "Chondrodendron tomentosum" in 1942, and it was shown that it was the active chemical in curare that had the paralysing effect. At that time it was known that curare and therefore d-tubocurarine worked at the neuromuscular junction. The isolation of tubocurarine and the marketing of it as the drug Intocostrin led to more research in the field of neuro-muscular blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance of the two quaternary ammonium compounds cite news | author=O.A.Nedergard, A et al | title=Curare:Flying death | date=2003 | publisher=Pharmacology & Toxicology 92, 154–155.] .

Further research led to the development of synthesized molecules with different curare form effects, depending on the distance between quaternary ammonium groups. One of the synthesized "bis"-quaternaries was decamethonium a 10-carbon "bis"-quaternary compound. Following research on decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl end. The discovery and development of suxamethonium lead to a Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in the way that its effect were achieved quicker and augmentated a response in the muscle before block. Also, tubocurarine effects were known to be reversible by acetylcholineesterase inhibitors, whereas decamethonium and suxamethonium block was not reversible .

Another compound malouétine that was a "dis"-quaternary steroid was isolated from the plant "Malouetia bequaertiana" and showed curare form activity. This led tho the synthetic drug pancuronium a "bis"-quaternary steroid and subsequently other chemicals that had better pharmacological properties as drugscite journal | journal = Anaesthesia | volume = 55 | issue = 6 | pages = 551–556 | year = 2000 | author = A. G. McKenzie | title = Prelude to pancuronium and vecuronium | doi = 10.1046/j.1365-2044.2000.01423.x] .

These molecules discussed above and research devoted to them led to many other compounds with different "pharmacological" properties and research in drug development as well as they helped to better the understanding the physiology of neurons and receptors.

Nomenclature

Neuromuscular blocking drugs are often classified into two broad classes:Pachycurares which are bulky molecules with nondepolarizing activity. Leptocurares are on the other hand thin and flexible molecules. They tend to have depolarizing activity . It is also common to classify them based on their chemical structure.

*Acetylcholine, succinylcholine, and decamethonium
Succinylcholine was synthesised by connecting two acetylcholine molecules and has the same number of heavy atoms between methonium heads as decamethonium. Just like acetylcholine, succinylcholine, decamethonium and other polymethylene chains, of the appropriate length and with two methonium, heads have small trimethyl onium heads and flexible links. They all show a depolarizing block.
* Aminosteroids
Pancuronium, vecuronium, rocuronium, rapacuronium, dacuronium, malouètine, duador, dipyrandium, pipecuronium, chandonium (HS-310), HS-342 and other HS- compounds are aminosteroidal agents. They have in common the steroid structural base which provides a rigid and bulky body. Most of the agents in this category would also be classified as non-depolarizing.
* Tetrahydroisoquinoline derivativesCompounds based on the tetrahydroisoquinoline moiety such as atracurium, mivacurium, and doxacurium would fall in this category. They have a long and flexible chain between the onium heads, except for the double bond of mivacurium. D-tubocurarine and dimethyltubocurarine are also in this category. Most of the agents in this category would be classified as non-depolarizing.
* Gallamine and other chemical classes
Gallamine is a trisquaternary ether with three ethonium heads attached to a phenyl ring through an ether linkage. Many other different structures have been used for their muscle relaxant effect such as alcuronium (alloferin), anatruxonium, diadonium, fazadinium (AH8165) and tropeinium.
*Novel NMB agentsIn recent years much research has been devoted to new types of quaternary ammonium muscle relaxants. These are asymmetrical diester isoquinolinium compounds and bis-benzyltropinium compounds that are bistropinium salts of various diacids. These classes have been developed to create muscle relaxants that are faster and shorter acting. Both the asymmetric structure of diester isoquinolinium compounds and the acyloxylated benzyl groups on the bisbenzyltropiniums destabilizes them and can lead to spontaneous breakdown and therefore possibly a shorter duration of action.

Mechanism of action

.

Non-depolarizing agentsA decrease in binding of acetylcholine leads to a decrease in its effect and neuron transmission to the muscle is less likely to occur. It is common understanding that non depolarizing agents block by acting as reversible competitive inhibitors. That is they bind to the receptor as antagonists and that leaves less receptors available for acetylcholine to bind to. cite news | author=L.L Brunton, J.S.Lazo, K.L.Parker | title=Goodman & Gilman's The pahrmacological basis of Therapeutics | date=2006 | publisher=New York:McGraw-Hill, Inc.p 220-223.] .

Depolarizing agents
Depolarizing agents produce their block by binding to and activating the receptor, causing contraction and after that paralysation. They bind to the receptor and cause depolarization by opening channels just like acetylcholine does. This causes repetitive excitation that lasts longer than a normal acetylcholine excitation and is most likely explained by depolarizing agents resistance to the enzyme acetylcholine esterase. The constant depolarization and triggering of the receptors keeps the endplate resistant to activation by acetylcholine. Therefor a normal neuron transmission to muscle can not cause contraction of the muscle because the endplate is depolarized and thereby the muscle paralysed.

Binding to the nicotinic receptor Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), will likely span the two receptive sites with one molecule (binding inter-site). Longer congeners will be required to bend when fitting the receptive sites.

The more energy a molecule needs to bend and fit will usually result in lower potency.cite journal | author= Lee, C.; Jones, T. | title=Molecular conformation–activity relationship of decamethonium congeners | year = 2002 | journal = British Journal of Anaesthesia | volume = 88 | issue = 5 | pages = 692–699 | url = http://bja.oxfordjournals.org/cgi/content/abstract/88/5/692 | doi=10.1093/bja/88.5.692]

Structural and conformational action relationship

It must be noted that conformational study on neuromuscular blocking drugs is relatively new and developing. Traditional SAR studies do not specify environmental factors on molecules. Computer based conformational searches assume the molecules to be "in vacuo" which is not the case "in vivo". Solvation models take into account the effect of a solvent on the conformation of the molecule. However, no system of solvation can mimic the effect of the complex fluid composition of the body cite journal | author = Lee, Chingmuh | year = 2003 | title = Conformation, action and mechanism of action of neuromuscular blocking muscle relaxants | journal = Pharmacology and Therapeutics | volume = 98 | pages = 143–169 | doi = 10.1016/S0163-7258(03)00030-5]

The division of muscle relaxants to rigid and non-rigid is at most qualitative. The energy required for conformational changes may give a more precise and quantitative picture. Energy required for reducing onium head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites Using computers it is possible to calculate the lowest energy state conformer and thus most populated and best representing the molecule. This state is referred to as the global minimum. The global minimum for some simple molecules can be discovered quite easily with certainty. Such as for decamethonium the straight line conformer is clearly the lowest energy state. Some molecules on the other hand have many rotatable bonds and their global minimum can only be approximated

Molecular length and rigidity

distance.

Generally molecular rigidity contributes to potency while size affects whether a muscle relaxant will show a polarizing or a depolarizing effect. Cations must be able to flow through the trans-membrane tube of the ion-channel to depolarize the endplate. Small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites. Large molecules on the other hand may bind to both receptive sites and hinder depolarizing cations independent of whether the ion-channel is open or closed below. Having a lipophilic surface pointed towards the synapse will enhance this effect by repelling cations. The importance of this effect varies between different muscle relaxants and classifying depolarizing from non-depolarizing blocks is a complex issue. The onium heads are usually kept small and the chains connecting the heads usually keep the N-N distance at 10 N or O atoms. Keeping the distance in mind the structure of the chain can vary (double bonded, cyclohexyl, benzyl, etc)

Succinylcholine has a 10 atom distance between its N atoms, like decamethonium, but yet it has been reported that it takes two molecules, as with acetylcholine, to open one nicotinic ion channel. The conformational explanation for this would be that each acetylcholine moiety of succinylcholine prefers the "gauche" (bent, cis) state. The attraction between the N and O atoms is grater than the onium head repulsion. In this most populated state the N-N distance will be shorter than the optimal distance of ten carbon atoms and to short to occupy both receptive sites. This similarity between succinyl- and acetyl-choline also explains its acetylcholine-like side effects.Comparing molecular lengths the pachycurares dimethyltubocurarine and d-tubocurarine which are both very rigid and both measure close to 1.8 nm in total length. Pancuronium and vecuronium measure 1.9 nm while pipecuronium is 2.1 nm. The potency of these compounds follows the same rank of order as their length. Likewise the leptocurares prefer a similar length. Decamethonium which measures 2 nm is the most potent in its category while C11 is slightly too long. Gallamine despite having low bulk and rigidity is the most potent in its class and it measures 1.9 nm. cite journal | author = Lee, C. | title = Structure, conformation and action of neuromuscular blocking drugs | year = 2001 | journal = British Journal of Anaesthesia | volume = 87 | issue = 5 | pages = 755–769 | url = http://bja.oxfordjournals.org/cgi/content/abstract/87/5/755 | doi = 10.1093/bja/87.5.755] Based on this information one can conclude that the optimum length for neuromuscular blocking agents, depolarizing or not, should be 2 to 2.1 nm.

The CAR for long chain bisquaternary tetrahydroisoquinolines like atracurium, cisatracurium, mivacurium and doxacurium is hard to determine because of their bulky onium heads and large number of rotatable bonds and groups. These agents must follow the same receptive topology as others which means that they don’t fit between the receptive sites without bending. Mivacurium for example has a molecular length of 3.6 nm when stretched out, far from the 2 to 2.1 nm optimum. Mivacurium, atracurium and doxacurium have greater N-N distance and molecular length than d-tubocurarine even when bent. To make them fit they have flexible connections that give their onium heads a chance to position themselves beneficially. This bent N-N scenario probably does not apply to laudexium and decamethylene bisatropium which prefer a straight conformation.

Beers and Reich's law

It has been concluded that acetylcholine and related compounds must be in the "gauche" (bent) configuration when bound to the nicotinic receptor.cite journal | author = Spivak, C.E, J.A. Waters and R.S Aronstam | year = 1989 | title = Binding of semirigid nicotinic agonists to nicotinic and muscarinic receptors | journal = Molecular Pharmacology | volume = 36 | issue = 1 | pages = 177–184 | url = http://molpharm.aspetjournals.org/cgi/content/abstract/36/1/177 | pmid = 2747625] ) Beers and Reich's studies on cholinergic receptors in 1970 showed a relationship affecting whether a compound was muscarinic or nicotinic. They showed that the distance from the centre of the quaternary N atom to the van der Waals extension of the respective O atom (or an equivalent H-bond acceptor) is a determining factor. If the distance is 0.44 nm then the compound will show muscarinic properties and if the distance is 0.59 nm then nicotinic properties will be dominant.cite journal | author = Beers, W.H and E. Reich | year = 1970 | title = Structure and Activity of Acetylcholine | journal = Nature | volume = 228 | pages = 917–922 | doi = 10.1038/228917a0] )

Rational design

Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action relationship data. A steroid skeleton was chosen because of its appropriate size and rigidness. Acetylcholine moieties were inserted to increase receptor affinity. Although having many unwanted side effects, a slow onset of action and recovery rate it was a big success and at the time the most potent neuromuscular drug available. Pancuronium and some other neuromuscular blocking agents block M2-receptors and therefore affect the vagus nerve leading to hypotension and tachycardia. This muscarinic blocking effect is related to the acetylcholine moiety on the A ring on pancuronium. Making the N atom on the A ring tertiary the ring loses its acetylcholine moiety and the resulting compound, vecuronium, has nearly 100 times less affinity to muscarin receptors while maintaining its nicotinic affinity‎ and a similar duration of action.‎ Vecuronium is therefore free from cardiovascular effects. ‎ The D ring shows excellent properties validating Beers and Reich's rule with great precision. As a result vecuronium has the greatest potency and specificity of all mono-quaternary compounds.

Potency

Two functional groups contribute significantly to aminosteroidal neuromuscular blocking potency, presumably to enable them to bind the receptor at two points. A bis-quaternary two point arrangement on A and D-ring (binding inter-site) or a D-ring acetylcholine moiety (binding at two points intra-site) are most likely to be successful. A third group can have variable effects. The quaternary and acetyl groups on the A and D ring of pipecuronium prevent it from binding intra-site (binding to two points at the same site). Instead it must bind as bis-quaternary (inter-site).These structures are very dissimilar from acetylcholine and free pipecuronium from nicotinic or muscarinic side effects linked to acetylcholine moiety. Also they protect the molecule from hydrolysis by cholinesterases, which explain its nature of kidney excretion. The four methyl-groups on the quaternary N atoms make it less lipophilic than most aminosteroids. This also affects pipecuroniums metabolism by resisting hepatic uptake, metabolism and biliary excretion. The length of the molecule (2.1 nm, close to ideal) and its rigidness make pipecuronium the most potent and clean one-bulk bis-quaternary. Even though the N-N distance (1.6 nm) is far away from what is considered ideal, its onium heads are well exposed and the quaternary groups help bringing together the onium heads to the anionic centers of the receptors without chirality issues.

Adding more than two onium heads in general does not add to potency. Although the third onium head in gallamine seems to help position the two outside heads near the optimum molecular length, it can interfere unfavorably and gallamine turns out to be a weak muscle relaxant like all multi-quaternary compounds.Considering acetylcholine a quaternizing group larger than methyl and an acyl group larger that acetyl would reduce the molecules potency. The charged N and the carbonyl O atoms are distanced from structures they bind to on receptive sites and thus decreasing potency. The carbonyl O in vecuronium for example is thrusted outward to appose the H-bond donor of the receptive site. This also helps explain why gallamine, rocuronium and rapacuronium are of relatively low potency.In general methyl quaternization is optimal for potency but opposing this rule the trimethyl derivatives of gallamine are of lower potency than gallamine. The reason for this is that gallamine has a suboptimal N-N distance. Substituting the ethyl groups with methyl groups would make the molecular length also shorter than optimal. Methoxylation of tetrahydroisoquinolinium agents seems to improve their potency. How methoxylation improves potency is still unclear.
Histamine release is a common attribute of benzylisoquinolinium muscle relaxants. This problem generally decreases with increased potency and smaller doses. The need for larger doses increases the degree of this side effect. Conformational or structural explanations for histamine release are not clear.

Pharmacokinetics

Metabolism and Hofman elimination

release.

Structure relations to onset time

The effect of structure on the onset of action is not very well known except that the time of onset seems to be inversely related to potency.cite journal | author =Kopman, Aaron F., Monica M. Klewicka, David J. Kopman and George G. Neuman| year = 1999 | title = Molar potency is predictive of the speed of onset of neuromuscular block for agents of intermediate, short and ultrashort duration| journal = Anesthesiology | volume = 90 | issue = 2 | pages = 425–431 | url = http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&dopt=AbstractPlus&list_uids=9952148 | doi = 10.1097/00000542-199902000-00016] In general "mono"-quaternary aminosteroids are faster than "bis"-quaternary compounds which means they are also of lower potency. A possible explanation for this effect is that drug delivery and receptor binding are of a different timescale. Weaker muscle relaxants are given in larger doses so more molecules in the central compartment must diffuse into the effect compartment, which is the space within the mouth of the receptor, of the body. After delivery to the effect compartment then all molecules act quickly.cite journal | author = Donati, F. and Claude Meistelman| year = 2005 | title =A kinetic-dynamic model to explain the relationship between high potency and slow onset time for neuromuscular blocking drugs| journal = Journal of pharmacokinetics and Pharmacodynamics | volume = 19 | issue = 5 | pages = 537–552| url = http://www.springerlink.com/content/j5527q19x6071106/] Therapeutically this relationship is very inconvenient because low potency, often meaning low specificity can decrease the safety margin thus increasing the chances of side effects. Additionally even though low potency usually accelerates onset of action it does not guaranty a fast onset. Gallamine for example is weak and slow. When fast onset is necessary then succinylcholine or rocuronium are usually preferable.

Elimination

Muscle relaxants can have very different metabolic pathways and it is important that the drug does not accumulate if certain elimination pathways are not active, for example in kidney failure.

References