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. In Vitro 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). MCE has not independently confirmed the accuracy of these methods. They are for reference only. In Vivo 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 . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Male Sprague-Dawley rats (70 days old; 260-300 g) injected with cocaineDosage: 10 mg/kg, 30 mg/kg Administration: i.p.; once Result: Produced dose-related reductions in cocaine self-administration. Form:Solid