mAChRs (muscarinic acetylcholine receptors) are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certainneurons and other cells. In addition, acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. There are five subtypes of muscarinic acetylcholine receptors that belong to class A of G-protein coupled receptors. The primary response of stimulation of the M2 and M4 subtypes of muscarinic receptors is activation of the Gi/o class of G-proteins resulting in inhibition of adenylyl cyclase, whereas stimulation of M1, M3, and M5 receptors leads to activation of the Gq/11 class of G-proteins and stimulation of phospholipase C.

Rapacuronium (also known as Org 9487), a non-depolarizing neuromuscular blocker, is an allosteric modulator of muscarinic acetylcholine receptor (mAChR). In addition, Rapacuronium shows facilitatory effects at muscarinic receptors. This compound binds to and exhibits negative cooperativity with acetylcholine (ACh) binding at all subtypes of muscarinic receptors. Surprisingly, low concentrations of Rapacuronium potentiate ACh-induced signaling at the M1, M3, and M5 receptor subtypes and accelerate ACh binding. Furthermore, Rapacuronium accelerates the rate of ACh binding but decreases its affinity under equilibrium conditions. This results in potentiation of receptor activation at low concentrations of rapacuronium (1 μM) but not at high concentrations (10 μM). In guinea pig experiments, Rapacuronium preferentially antagonized M2 but not M3 muscarinic receptors. Moreover, Rapacuronium potentiates bronchoconstriction evoked by both naturally released and exogenous acetylcholine, indicating an important role of postsynaptic M3 receptors.

To sum up, Rapacuronium, a non-depolarizing neuromuscular blocker, is an allosteric modulator of mAChRs.


[1] Jan Jakubík, et al. BMC Pharmacol. 2009 Dec 28;9:15.