Discovery of the First α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent upon Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8

Abstract

Transmembrane AMPA receptor regulatory proteins (TARPs) are a family of scaffolding proteins that regulate AMPA receptor trafficking and function. TARP γ-8 is one member of this family and is highly expressed within the hippocampus relative to the cerebellum. A selective TARP γ-8-dependent AMPA receptor antagonist (TDAA) is an innovative approach to modulate AMPA receptors in specific brain regions to potentially increase the therapeutic index relative to known non-TARP-dependent AMPA antagonists. We describe here, for the first time, the discovery of a noncompetitive AMPA receptor antagonist that is dependent on the presence of TARP γ-8. Three major iteration cycles were employed to improve upon potency, CYP1A2-dependent challenges, and in vivo clearance. An optimized molecule, compound (-)-25 (LY3130481), was fully protective against pentylenetetrazole-induced convulsions in rats without the motor impairment associated with non-TARP-dependent AMPA receptor antagonists. Compound (-)-25 could be utilized to provide proof of concept for antiepileptic efficacy with reduced motor side effects in patients.

TARP γ-2 Is Required for Inflammation-Associated AMPA Receptor Plasticity within Lamina II of the Spinal Cord Dorsal Horn

“…It is noteworthy that an understanding of TARP expression in nociceptive circuitry may reveal novel therapeutic targets, in that TARPs endow AMPARs with a unique pharmacology. For example, two antagonists have recently been developed that selectively block AMPARs associated with γ-8 (Gardinier et al, 2016; Maher et al, 2016). Development of other TARP-selective drugs may increase the resolution of AMPAR-targeted pain therapies and aid in treating the maladaptive aspects of pain while retaining the basic nociceptive signaling necessary for survival.…”

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

“…Negative modulation of AMPA receptor γ8 offers the possibility of selectively reducing excitatory transmission within brain circuits associated with epilepsy. Both Lilly/Cerecor and Janssen Research & Development have disclosed compounds targeting AMPA receptor γ8 …”

“…JNJ-40411813 also displays binding to human 5HT 2A receptors in vitro (K b = 1.1 μmol/L). In a Ca ++ mobilization assay in human embryonic kidney cells transfected with human mGlu2, JNJ-40411813 had an EC 50 of 64 ± 29 nmol/L, and in vitro Ca ++ and [ 35 S]GTPgammaS assays demonstrated that JNJ-40411813 is >50-fold more selective for mGlu2 than other mGlu receptor members.…”

“…Both Lilly/Cerecor and Janssen Research & Development have disclosed compounds targeting AMPA receptor γ8. 35,36 JNJ-55511118 is a selective negative modulator of AMPA receptor γ8, with approximately 1000× selectivity versus AMPA receptors containing other TARPs (eg, γ2, γ4) or versus TARP-less receptors. In in vitro electrophysiological studies using hippocampal neurons, JNJ-55511118 at a 1 μmol/L concentration only partially reduces AMPA receptor peak responses.…”

AMPA Receptor Positive Allosteric Modulators: Potential for the Treatment of Neuropsychiatric and Neurological Disorders

“…This would be achieved by identifying TARP-dependent AMPAR PAMs and a similar strategy has recently been successfully implemented by Lilly in their search for safer AMPAR antagonists for the treatment of epilepsy. [43] Positive emission tomography studies with a range of AMPAR modulators have indicated that different concentrations of potentiators are required to selectively activate the CNS regions associated with procognitive and undesired effects, suggesting a potential role of localized auxiliary proteins resulting in AMPAR complexes with different biophysical properties [44].…”