Rapacuronium bromide

Rapacuronium bromide (Org 9487), a non-depolarizing neuromuscular blocker, is an allosteric modulator of muscarinic acetylcholine receptor (mAChR)^[1]. IC50 & Target: Muscarinic receptor^[1] In Vitro: Rapacuronium binds to all muscarinic receptor subtypes at physiologically relevant concentrations and displays micromolar affinity and slight selectivity towards M₂ receptor. Rapacuronium exhibits complex effects on the kinetics of ACh binding and subsequent receptor activation estimated from stimulation of [³⁵S]GTPγS binding. Rapacuronium alone concentration dependently lowers [³⁵S]GTPγS binding to membranes with a maximal effect of approximately 25% at odd-numbered subtypes and 15% at even-numbered subtypes, with EC₅₀ ranging from 28 μM at M₂ receptors to 76 μM at M₃ receptors. While the EC₅₀ values of Rapacuronium in inhibiting [³⁵S]GTPγS binding at individual subtypes correlated with affinities measured in binding experiments with [³H]ACh (R² = 0.76) they are lower (4- to 12-fold) at all subtypes. Measurements of ACh-stimulated [³⁵S]GTPγS binding in the presence of 0.1, 1 and 10 μM Rapacuronium shows differential effects of Rapacuronium on receptor activation by an orthosteric agonist at individual receptor subtypes. At even-numbered subtypes 1 μM and 10 μM Rapacuronium significantly increases ACh EC₅₀, with lowering of E_MAX at 10 μM Rapacuronium. At this subtype 0.1 and 1 μM Rapacuronium causes a significant 2-fold decrease in ACh EC₅₀ and approximately 60% and 35% increase in E_MAX, respectively. Rapacuronium at 10 μM increases ACh EC₅₀ by about 3-fold without a significant change in E_MAX. Rapacuronium (0.1 - 10 μM) has no effect on ACh efficacy at the M₁ and M₅ subtypes but decreases the EC₅₀ of ACh in stimulating [³⁵S]GTPγS binding by 1.5- and 4-fold, respectively, at concentrations of 0.1 and 1 μM. However, this effect is not evident at 10 μM Rapacuronium^[1]. In Vivo: Time course of the neuromuscular effects of Rapacuronium following the administration of the 2×ED₉₀ doses to rats and guinea-pigs with ED₉₀ of 5953±199 and 187±16 µg/kg in rat and guinea pig, respectively^[2].