| Bioactivity | VU6019650 is a potent and selective orthosteric antagonist of M5 mAChR (IC50=36 nM), can be used for opioid use disorder (OUD) relief. VU6019650 can cross blood brain barrier, potentially modulates the mesolimbic dopaminergic reward circuitry. VU6019650 blocks Oxotremorine M iodide (HY-101372A) induced increases of neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area (VTA)[1][2]. | ||||||||||||
| Invitro | VU6019650 (0-10 μM) 对 M5 的选择性 (IC50=36 nM) 高于对其他亚型 (是对人 M1-4 的选择性的 100倍)[1]。VU6019650 (1 μM) 能够阻断 Oxo-M 诱导的 VTA 神经元激活[1]。VU6019650 表现出脑透过性，在大鼠脑和血浆中的 Kp，Kp, uu 值分别为 0.27 和 0.43[1]。 | ||||||||||||
| In Vivo | VU6019650 (10-56.6 mg/kg; 腹腔注射; 单次剂量) 抑制 Oxycodone 的奖励效应，减少大鼠受 Oxycodone 影响产生的自我给药现象[1]。在大鼠中的药代动力学分析[1]Route | ||||||||||||
| Name | VU6019650 | ||||||||||||
| Formula | C18H22FN3O3S2 | ||||||||||||
| Molar Mass | 411.51 | ||||||||||||
| Appearance | Solid | ||||||||||||
| Transport | Room temperature in continental US; may vary elsewhere. | ||||||||||||
| Storage |
|
||||||||||||
| Reference | [1]. Garrison AT, et al. Development of VU6019650: A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder. J Med Chem. 2022 Apr 28;65(8):6273-6286. [2]. Capstick RA, et al. Discovery of a potent M5 antagonist with improved clearance profile. Part 1: Piperidine amide-based antagonists. Bioorg Med Chem Lett. 2022 Nov 15;76:128988. |