156137-99-4

Muscarinic receptor

Rapacuronium binds to all muscarinic receptor subtypes at physiologically relevant concentrations and displays micromolar affinity and slight selectivity towards M ₂ receptor. Rapacuronium exhibits complex effects on the kinetics of ACh binding and subsequent receptor activation estimated from stimulation of [ ³⁵ S]GTPγS binding. Rapacuronium alone concentration dependently lowers [ ³⁵ S]GTPγS binding to membranes with a maximal effect of approximately 25% at odd-numbered subtypes and 15% at even-numbered subtypes, with EC ₅₀ ranging from 28 μM at M ₂ receptors to 76 μM at M ₃ receptors. While the EC ₅₀ values of Rapacuronium in inhibiting [ ³⁵ S]GTPγS binding at individual subtypes correlated with affinities measured in binding experiments with [ ³ H]ACh (R ² = 0.76) they are lower (4- to 12-fold) at all subtypes. Measurements of ACh-stimulated [ ³⁵ S]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 EC ₅₀ , 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 EC ₅₀ and approximately 60% and 35% increase in E _MAX , respectively. Rapacuronium at 10 μM increases ACh EC ₅₀ by about 3-fold without a significant change in E _MAX . Rapacuronium (0.1 - 10 μM) has no effect on ACh efficacy at the M ₁ and M ₅ subtypes but decreases the EC ₅₀ of ACh in stimulating [ ³⁵ S]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.

Time course of the neuromuscular effects of Rapacuronium following the administration of the 2×ED ₉₀ doses to rats and guinea-pigs with ED ₉₀ of 5953±199 and 187±16 µg/kg in rat and guinea pig, respectively.