Preclinical characterization of a water-soluble low-impact ampakine prodrug, CX1942 and its active moiety, CX1763

<b>Aim:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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. The water-soluble glycine ester pro-drug of CX1763, CX1942 is potent and active against alfentanil-induced respiratory depression <i>in vivo</i> CX1942 and CX1763 produce a durable increase in hippocampal EPSP <i>in vivo</i> CX1763 increases metrics of attention in rodents while reducing hyperactivity associated with amphetamine, indicating multiple potential benefits for ADHD treatment CX1763/CX1942 is therapeutically active at doses of 2.5–10 mg/kg and CX1763 lacks epileptic and fatal toxicities up to 1500 mg/kg, demonstrating a notable safety margin, justifying further preclinical and clinical explorations

【研究目的】AMPA-谷氨酸受体（AMPA-glutamate receptor, AMPAR）功能失调可介导多种神经及神经精神疾病。安帕金（Ampakines）可结合AMPAR，并通过变构调节增强谷氨酸诱导的电流。本研究报道了水溶性安帕金类前药CX1942及其活性组分CX1763的活性。【实验结果】CX1763与CX1942可增强大鼠海马脑区的突触传递功能。CX1763可提升大鼠在五选择连续反应时任务（5CSRTT）中的注意力水平，并降低小鼠苯丙胺诱导的多动行为。CX1942可强效逆转大鼠阿片类药物诱导的呼吸抑制。CX1942/CX1763的有效给药剂量为2.5~10 mg/kg。在大鼠中，CX1763在剂量高达1500 mg/kg时未表现出致痫性。【研究结论】本研究数据表明，CX1942与CX1763在多项临床前实验中均具有生物学活性，且无显著不良反应。CX1942可作为CX1763的前药，其优势在于水溶性优异，可用于静脉给药制剂。作为CX1763的水溶性甘氨酸酯前药，CX1942在体内可强效对抗阿芬太尼诱导的呼吸抑制。CX1942与CX1763在体内可持久增强海马脑区的兴奋性突触后电位（EPSP）。CX1763可提升啮齿类动物的注意力相关指标，同时减轻苯丙胺诱导的多动行为，提示其在注意缺陷多动障碍（ADHD）治疗中具备多重潜在应用价值。CX1763/CX1942在2.5~10 mg/kg剂量范围内具有治疗活性，且CX1763在剂量高达1500 mg/kg时无致痫性及致死性毒性，展现出显著的安全边际，为后续开展临床前及临床探索研究提供了依据。