2018
DOI: 10.1111/cns.13046
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Pronounced antiepileptic activity of the subtype‐selective GABAA‐positive allosteric modulator PF‐06372865 in the GAERS absence epilepsy model

Abstract: PF-06372865 demonstrated robust efficacy in suppressing SWDs in the GAERS model of absence epilepsy. To our knowledge, this is the first demonstration of antiepileptic activity of an α2/3/5-subtype-selective GABA PAM in a model of absence epilepsy. Further study of the antiepileptic properties of PF-06372865 is warranted in patients with absence seizures.

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Cited by 24 publications
(30 citation statements)
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“…35 There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL-865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD. 35 In addition, agents like CVL-865 with lower intrinsic activity could be associated with a reduced potential for tolerance induction, as previously demonstrated for other subtype-selective PAMs in animal models. 36 Efficacy in preclinical epilepsy models and in the clinical photosensitive epilepsy model supports the hypothesis that antiseizure activity can be attained with CVL-865, presumably by achieving high receptor occupancy at α2-containing subunits.…”
Section: Mechanism Of Actionmentioning
confidence: 99%
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“…35 There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL-865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD. 35 In addition, agents like CVL-865 with lower intrinsic activity could be associated with a reduced potential for tolerance induction, as previously demonstrated for other subtype-selective PAMs in animal models. 36 Efficacy in preclinical epilepsy models and in the clinical photosensitive epilepsy model supports the hypothesis that antiseizure activity can be attained with CVL-865, presumably by achieving high receptor occupancy at α2-containing subunits.…”
Section: Mechanism Of Actionmentioning
confidence: 99%
“…The ability to achieve high receptor occupancy with a subtype‐selective PAM such as CVL‐865 is believed to be an important component of attaining efficacy. Nonselective BZDs are not full agonists at the BZD site of GABA A receptors but are highly effective PAMs with high intrinsic activity, which presumably enables efficacy to be observed in epilepsy with low (<20%) receptor occupancy 35 . There is preclinical evidence in models of anxiety and epilepsy that PAMs with lower intrinsic activity at the BZD binding site such as CVL‐865 need to occupy a greater proportion of the receptors to produce the same magnitude of pharmacological activity as a BZD 35 .…”
Section: Cvl‐865mentioning
confidence: 99%
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“…44 In addition, PF-06372865 dose-dependently reduced the number of spike-and-wave discharges in the genetic absence epilepsy rats from Strasbourg (GAERS). 48 The rat half-life of 5.5 h for PF-06372865 translated into a half-life in man of 6.0-8.9 h over a dose range of 0.04 to 100 mg in an oral suspension. 45 Doses of 10 and 65 mg gave whole brain GABAAR occupancy of 69 and 89% in a [ 11 C]flumazenil PET study and there were dose-dependent effects on a number of pharmacodynamic parameters, including saccadic peak velocity, qEEG and a slight increase in body-sway, with the latter possibly being related to sedation and/or myorelaxation that was α1-GABAAR-mediated.…”
Section: α2/α3-gabaar Pamsmentioning
confidence: 99%
“…38 Other substances with positive allosteric modulatory action selective for GABA A receptors with α 2 /α 3 subunits that showed anticonvulsant effects in animal models of epilepsy are: AZD7325 (4-amino-8-(2-fluoro-6-methoxy-phenyl) -N-propyl-cinnoline-3-carboxamide), which increased the threshold for hyperthermia-induced seizures in Scn1a +/− mice, 39 and PF-06372865 (7-ethyl-4-[3-(4-ethylsulfonyl-2-methoxyphenyl)-4-fluorophenyl]imidazo[4,5-c]pyridazine), which efficiently suppressed spike-and-wave discharges in rats genetically prone to absence seizures (Genetic Absence Epilepsy Rats from Strasbourg [GAERS] strain). 40 However, only the latter found its way into clinical trials, and is now known under the name CVL-865.…”
Section: Gaba a Receptor Agonists And Allosteric Modulators In Preclimentioning
confidence: 99%