Methoctramine is a polymethylene tetraamine that acts as amuscarinicantagonist. It preferentially binds to the pre-synaptic receptorM2, a muscarinic acetylcholine ganglionic protein complex present basically in heart cells. In normal conditions -absence of methoctramine-, the activation of M2 receptors diminishes the speed of conduction of thesinoatrial andatrioventricular nodes thus reducing the heart rate. Thanks to its apparently high cardioselectivity, it has been studied as a potentialparasymphatolitic drug, particularly against bradycardia. However, currently it is only addressed for research purposes, since the administration to humans is still unavailable.
Methoctramine has been shown to competitively antagonize muscarinic receptors, thus preventing them from binding to the neurotransmitter acetylcholine (and other agonists, such asbethanechol orberberine). At higher concentrations, allosteric properties of methoctramine have also been described.[1]
Biochemical literature distinguishes 5 different types of muscarinic receptors, each of one having a different affinity to methoctramine:
Muscarinic receptor subtype
M1
M2
M3
M4
M5
Affinity constants (nM) in Chinese hamster ovary cells.[2]
50
13.2
214
31.6
135
The lower the affinity constants are, the more affinity exists.
As shown in the chart above, methoctramine binds preferently to M2 receptors, found mostly in the parasympathetic nerves and atria. There, the activity it develops is clearly related to the contraction process. In presence of acetylcholine, M2 receptors are believed to play an autoinhibitory role in the atria, triggering processes that prevent contraction from occurring. Hence, the presence of the antagonist methoctramine provokes an increase of the heart rate.
In marked contrast of the above, methoctramine has the opposite function in other organs: it inhibits contraction. This occurs especially in the bladder, where, unlike the heart, autoinhibitory processes of this type do not exist.
Recent research, however, led to find the mentioned specialty dubious, rising the possibility of it binding to other types of receptors, such as nicotinic ACh receptors –at micromolar concentrations- or adenosine A3.
Still object of investigation, methoctramine has not been introduced in the pharmacological industry yet. Research conducted in mice (and other animals), suggests nonetheless many clinical uses of it, thanks to its implications in contraction processes. These applications include, but are not limited to:
Combat bladder overactivity, because it triggers effects that enhance its relaxation.[4]
Memory improvements in cognitively impaired patients.[5]
Methoctramine was shown to produce somecytotoxic effects,[8] being the cardiomyoblasts the most sensitive cells reported. Cell death occurs only at high micromolar concentrations (being the average pharmacological dose at nanomolar level). From all the methoctramine-derived polymers, those with more spacing between the inner nitrogen atoms were shown to have the lowest lethal doses.
This mentioned toxicity has its origin in a non-muscarinic mechanism, and bears a strong resemblance to otheranticholinergic drugs, such asgallamine.
There’s evidence thatlithium could act as an antidote against methoctramine.[9]
^Jakubík J, Zimčík P, Randáková A, Fuksová K, El-Fakahany EE, Doležal V (August 2014). "Molecular mechanisms of methoctramine binding and selectivity at muscarinic acetylcholine receptors".Molecular Pharmacology.86 (2):180–92.doi:10.1124/mol.114.093310.PMID24870405.
^Schwartz W.J.(1997). Frontiers of Neurology and Neuroscience, Vol.15 Sleep Science: Integrating Basic Research and Clinical Practice. Worcester(Massachusetts). Karger.ISBN978-3-8055-6537-0
^Gómez-Martínez LE, Cueva-Rolón R (November 2009). "Muscarinic receptor antagonism at the spinal cord level causes inhibitory effects on male rat sexual behavior".Behavioural Brain Research.203 (2):247–55.doi:10.1016/j.bbr.2009.05.010.PMID19450623.
^Lazaris A, Cassel S, Stemmelin J, Cassel JC, Kelche C (2004). "Intrastriatal infusions of methoctramine improve memory in cognitively impaired aged rats".Neurobiology of Aging.24 (2):379–83.doi:10.1016/s0197-4580(02)00067-2.PMID12498972.
^Wess J, Angeli P, Melchiorre C, Moser U, Mutschler E, Lambrecht G (September 1988). "Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo".Naunyn-Schmiedeberg's Archives of Pharmacology.338 (3):246–9.doi:10.1007/bf00173395.PMID3057387.
