**Background**
Excitotoxicity, driven by the overactivation of ionotropic glutamate receptors, plays a critical role in the pathogenesis of various neurological disorders, including stroke, traumatic brain injury, and epilepsy. Among these receptors, the $\alpha$-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors are primary mediators of fast excitatory synaptic transmission in the central nervous system. Excessive activation of these receptors leads to an uncontrolled influx of cations, resulting in neuronal damage and death. Therefore, the development of highly selective antagonists that can block AMPA/kainate receptors without interfering with N-methyl-D-aspartate (NMDA) receptors is essential for achieving neuroprotection while minimizing cognitive side effects. In this context, we will introduce a selective AMPA/kainate antagonist – Fanapanel.
**Definition**
Fanapanel (also known as ZK200775) is a highly selective AMPA/kainate antagonist that exhibits minimal activity against NMDA receptors, with $K_i$ values of 3.2 nM and 100 nM against quisqualate and kainate, respectively.
**In Vitro and In Vivo Studies**
According to the Fanapanel description, this compound is a phosphonate quinoxalinedione derivative. In terms of Fanapanel in vitro activity, cortical slice preparation assays demonstrated $K_i$ values of 3.2 nM for quisqualate, 100 nM for kainate, and 8.5 $\mu$M for NMDA. Furthermore, in spreading depression assays, Fanapanel exhibited $IC_{50}$ values of 200 nM against quisqualate, 76 nM against kainate, 13 $\mu$M against NMDA, and 18 $\mu$M against glycine.
Regarding Fanapanel in vivo efficacy, the compound significantly elevated the threshold for AMPA- and kainate-induced clonic seizures in mice, with $THRD_{50}$ values of 2.9 (1.7–4.6) mg/kg and 1.6 (1.3–2.0) mg/kg i.v., respectively. In contrast, the threshold for NMDA-induced seizures was only elevated at much higher doses ($THRD_{50}$ of 24.1 mg/kg i.v.), which also impaired motor coordination. Additionally, doses of 10 and 30 mg/kg i.v. were found to reduce muscle tone in genetically spastic rats. Research also indicated that Fanapanel (3.0 mg/kg) significantly decreased nicotine-induced dopamine (DA) release in the nucleus accumbens (NAcc) and nicotine-stimulated locomotor activity (LMA), while showing 34-fold selectivity for AMPA receptors over NMDA receptors. In conclusion, Fanapanel is a potent and selective AMPA/kainate antagonist with significant potential for neuroprotection and the treatment of spasticity.
Keywords
Fanapanel, 161605-73-8, ZK200775, MPQX, ZK 200775, ZK-200775, iGluR, Ionotropic glutamate receptors, Inhibitor, inhibitor, inhibit
References
[1] Turski L, et al. ZK200775: a phosphonate quinoxalinedione AMPA antagonist for neuroprotection in stroke and trauma. Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10960-5.
[2] Kosowski AR, et al. Nicotine-induced dopamine release in the nucleus accumbens is inhibited by the novel AMPA antagonist ZK200775 and the NMDA antagonist CGP39551. Psychopharmacology (Berl). 2004 Aug;175(1):114-23.