ML375 (VU0483253) is a potent, highly selective, brain-penetrant and orally active M5 mAChR negative allosteric modulator (NAM) with IC₅₀s of 300 nM and 790 nM for human and rat M5, respectively. ML375 is inactive at human and rat M1-M4.

ML375 possesses high metabolic stability with low hepatic microsomal intrinsic clearance (CL_int; 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 (CL_hep; human, 2.3 mL/min/kg, cyno, 14 mL/min/kg rat, 18 mL/min/kg).

西域 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.

西域 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.

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

• . 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  [Content Brief]

  . 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.  [Content Brief]