Tiotropium Bromide Binding to Muscarinic (M3) Acetylcholine Receptor
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Tiotropium bromide (Spiriva™) is a long acting, inhaled anti-cholinergic agent used for maintenance of chronic obstructive pulmonary disease (COPD). Tiotropium bromide acts by competitively and reversibly inhibiting muscarinic receptors M1, M2, and M3. This mechanism of action causes bronchodilation and relaxation of smooth muscle in the lungs. The tiotropium bromide molecular structure provides higher binding specificity to the M3 receptor when locally administered. Our goal was to clarify the interactions between the tiotropium molecule and its receptors.
Once the tiotropium bromide molecule encounters the receptor, it binds deep inside the core and is covered by a tyrosine lid. The tyrosine lid creates an environment where the drug can interact with the hydrophobic regions inside the receptor.
The M3 receptor has a leucine in the ECL2 portion of the binding site, unlike M2 which has a phenylalanine in the ECL2 portion. The substitution creates a larger binding pocket which does not cause a disruption of the hydrogen bond created by the thiophene ring of tiotropium bromide and the tyrosine of the receptor. This unique interaction accounts for its higher affinity and slower dissociation of tiotropium bromide from the M3 receptor and provides a 24-hour duration of action.
The antagonist action of tiotropium bromide on the M1, M2, and M3 receptors creates an anti-cholinergic effect in the body. The M3 receptor drug target of COPD is located in the lungs, making inhaled medication a first-line therapy due to quick and local delivery of the drug. Inhibition of the M1, M2, and M3 receptors reduces secretions and airway constriction in the lungs, giving the patient reduced COPD symptoms.
We clarified that tiotropium bromide has higher affinity to the M3 receptor which promotes a longer duration of action and limits side effects. Our patient was given tiotropium bromide rather than aclidinium bromide due to the highly specific inhibition of the M3 receptor and the once daily regimen. A Respimat™ dosage form was chosen for the ease of use and reduced side effects.