ML375 (VU0483253) 是一种有效、高选择性、可透过血脑屏障和具有口服活性的 M5 mAChR 负变构调节剂 (NAM)，对人和大鼠 M5 的 IC₅₀ 分别为 300 nM 和 790 nM。ML375 对人和大鼠的 M1-M4 无活性。

ML375 (VU0483253) is a potent, highly selective, brain-penetrant and orally active M5 mAChR negative allosteric modulator (NAM) with IC 50 s of 300 nM and 790 nM for human and rat M5, respectively. ML375 is inactive at human and rat M1-M4.

Solid

ML375 possesses high metabolic stability with low hepatic microsomal intrinsic clearance (CLint; human 2.6 mL/min/kg, cynomolgus monkey (cyno), 20 mL/min/kg, rat, 24 mL/min/kg) and a corresponding low predicted hepatic clearance in multiple species (CLhep; human, 2.3 mL/min/kg, cyno, 14 mL/min/kg rat, 18 mL/min/kg). has not independently confirmed the accuracy of these methods. They are for reference only.

ML375 (10-30 mg/kg; i.p.; once) attenuates both the reinforcing effects and the relative strength of cocaine.
ML375 exhibits low clearance (CL p , 2.5 mL/min/kg) and a long elimination half-life (T 1/2 , 80 hr) in rodents (male, Sprague-Dawley rat, 1 mg/kg IV,) and nonhuman primates (male, cynomolgus monkey, 1 mg/kg, CL p , 3.0 mL/min/kg, T 1/2 , 10 hr).
ML375 also demonstrates high oral bioavailability (%F, 80) following administration of a suspension-dose to male SD rats with a maximal plasma concentration (C max ) of 1.4 μM and a corresponding time to reach C max (T max ) of 7 hours. has not independently confirmed the accuracy of these methods. They are for reference only.

Room temperature in continental US; may vary elsewhere.

Powder -20°C 3 years；4°C 2 years

[1]. Patrick R Gentry, et al. Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML
[2]. Barak W Gunter, et al. Selective inhibition of M 5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats. Addict Biol. 2018 Sep;23(5):1106-1116.