| Bioactivity | 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[1]. | ||||||||||||
| Invitro | 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)[1]. | ||||||||||||
| In Vivo | ML375 (10-30 mg/kg; i.p.; once) attenuates both the reinforcing effects and the relative strength of cocaine[2].ML375 exhibits low clearance (CLp, 2.5 mL/min/kg) and a long elimination half-life (T1/2, 80 hr) in rodents (male, Sprague-Dawley rat, 1 mg/kg IV,) and nonhuman primates (male, cynomolgus monkey, 1 mg/kg, CLp, 3.0 mL/min/kg, T1/2, 10 hr)[1]. ML375 also demonstrates high oral bioavailability (%F, 80) following administration of a suspension-dose to male SD rats with a maximal plasma concentration (Cmax) of 1.4 μM and a corresponding time to reach Cmax (Tmax) of 7 hours[1]. Animal Model: | ||||||||||||
| Name | ML375 | ||||||||||||
| CAS | 1488362-55-5 | ||||||||||||
| Formula | C23H15ClF2N2O2 | ||||||||||||
| Molar Mass | 424.83 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
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| Reference | [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. |
ML375
CAS: 1488362-55-5 F: C23H15ClF2N2O2 W: 424.83
ML375 (VU0483253) is a potent, highly selective, brain-penetrant and orally active M5 mAChR negative allosteric modulato
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