385367-47-5

Tarafenacin(SVT-40776) is a highly selective M3 muscarinic receptor antagonist (Ki= 0.19 nM), ~200 fold selectivity over M2 receptor. IC50 value: 0.19 nM (Ki) [1] Target: M3 muscarinic receptor in vitro: SVT-40776 is highly selective for M(3) over M(2) receptors (Ki = 0.19 nmol.L(-1) for M(3) receptor affinity). SVT-40776 was the most potent in inhibiting carbachol-induced bladder contractions of the anti-cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT-40776 exhibited the highest urinary versus cardiac selectivity (199-fold) [1]. SVT-40776 has a much higher binding affinity (K(d) = 0.4 nM) to M5 mAChR than that of solifenacin (K(d) = 31 nM) with the same reeptor. The calculated binding free energy change (-2.3 ± 0.3 kcal/mol) from solifenacin to SVT-40776 is in good agreement with the experimentally derived binding free energy change (-2.58 kcal/mol), suggesting that our modeled M5 mAChR structure and its complexes with the antagonists are reliable [2]. in vivo: In the guinea pig in vivo model, SVT-40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 microg.kg(-1) i.v), without affecting arterial blood pressure [1].

tarafenacin is a selective antagonist of m3 muscarinic receptor with ki value of 0.19nm [1].tarafenacin is a novel quinuclidine derivative and is developed as an antimuscarinic drug for treatment of overactive bladder. it shows a 203-fold selectivity with m3 receptor over m2 receptor. tarafenacin reduces the maximum carbachol response at concentrations of 10nm and 100nm in mouse isolated bladder. in mouse atrial preparations, tarafenacin slightly attenuates the effects on heart rate caused by carbachol. tarafenacin shows a 199-fold urinary affinity against cardiac affinity. it is a highly potent antagonist in the bladder and lacks any relevant effect in atria at the same range of concentrations. in the guinea pig model, tarafenacin significantly changes the bladder contraction amplitude. it inhibits 25% of spontaneous bladder contractions at dose of 17.1nmol/kg [1].

mAChR3

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[1] salcedo c, davalillo s, cabellos j, et al. in vivo and in vitro pharmacological characterization of svt-40776, a novel m3 muscarinic receptor antagonist, for the treatment of overactive bladder. british journal of pharmacology, 2009, 156(5): 807-817.