Radin Daniel P, Zhong Sheng, Cerne Rok, Shoaib Mohammed, Witkin Jeffrey M, Lippa Arnold
RespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452, USA.
Psychogenics, 215 College Road, Paramus, NJ 07652, USA.
Future Med Chem. 2024;16(22):2325-2336. doi: 10.1080/17568919.2024.2401312. Epub 2024 Sep 20.
AMPA-glutamate receptor (AMPAR) dysfunction mediates multiple neurological/neuropsychiatric disorders. Ampakines bind AMPARs and allosterically enhance glutamate-elicited currents. This report describes the activity of the water-soluble ampakine CX1942 prodrug and the active moiety CX1763. CX1763 and CX1942 enhance synaptic transmission in hippocampi of rats. CX1763 increases attention in the 5CSRTT in rats and reduces amphetamine-induced hyperactivity in mice. CX1942 potently reverses opioid-induced respiratory depression in rats. CX1942/CX1763 was effective at 2.5-10 mg/kg. CX1763 lacked epileptogenicity up to 1500 mg/kg in rats. These data document that CX1942 and CX1763 are active and without prominent side effects in multiple pre-clinical assays. CX1942 could serve as a prodrug for CX1763 with the advantage of high water solubility as in an intravenous formulation.
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPA受体）功能障碍介导多种神经/神经精神疾病。安帕金与AMPA受体结合并变构增强谷氨酸引发的电流。本报告描述了水溶性安帕金CX1942前药和活性部分CX1763的活性。CX1763和CX1942增强大鼠海马体中的突触传递。CX1763提高大鼠在5选串行反应时任务中的注意力，并减少小鼠中苯丙胺诱导的多动。CX1942有效逆转大鼠中阿片类药物诱导的呼吸抑制。CX1942/CX1763在2.5-10mg/kg时有效。在大鼠中，高达1500mg/kg的CX1763没有致癫痫性。这些数据证明CX1942和CX1763具有活性，并且在多种临床前试验中没有明显副作用。CX1942可以作为CX1763的前药，具有高水溶性的优点，如在静脉制剂中。
