Binding Characteristics and Analgesic Effects of Mirogabalin, a Novel Ligand for the α2δ Subunit of Voltage-Gated Calcium Channels.

Yuki Domon,Kiyonori Kai,Yutaka Kitano,Tatsuya Inoue,Naotoshi Yamamura,Naohisa Arakawa,Fumihiko Matsuda,Makoto Takahashi

doi:10.1124/jpet.117.247551

Abstract

Mirogabalin ([(1R,5S,6S)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the α2δ subunit of voltage-gated calcium channels, is being developed to treat pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. In the present study, we investigated the in vitro binding characteristics and in vivo analgesic effects of mirogabalin compared with those of pregabalin, a standard α2δ ligand. Mirogabalin showed potent and selective binding affinities for the α2δ subunits, while having no effects on 186 off-target proteins. Similar to pregabalin, mirogabalin did not show clear subtype selectivity (α2δ-1 vs. α2δ-2) or species differences (human vs. rat). However, in contrast to pregabalin, mirogabalin showed greater binding affinities for human α2δ-1, human α2δ-2, rat α2δ-1, and rat α2δ-2 subunits; further, it had a slower dissociation rate for the α2δ-1 subunit than the α2δ-2 subunit. Additionally, in experimental neuropathic pain models, partial sciatic nerve ligation rats and streptozotocin-induced diabetic rats, mirogabalin showed more potent and longer lasting analgesic effects. In safety pharmacological evaluations, mirogabalin and pregabalin inhibited rota-rod performance and locomotor activity in rats; however, the safety indices of mirogabalin were superior to those of pregabalin. In conclusion, mirogabalin shows potent and selective binding affinities for the human and rat α2δ subunits, and slower dissociation rates for the α2δ-1 subunit than the α2δ-2 subunit. It shows potent and long-lasting analgesic effects in rat models of neuropathic pain, and wider safety margins for side effects of the central nervous system. These properties of mirogabalin can be associated with its unique binding characteristics.

Highlights

Gabapentinoids, such as pregabalin and gabapentin, are selective ligands for the a2d subunit of voltage-gated calcium channels (Li et al, 2011; Alexander et al, 2015)
Increased expression of a2d-1 mRNA and a2d-1 protein has been observed in the dorsal root ganglion and the spinal cord dorsal horn of rat models for neuropathic pain (Luo et al, 2001; Newton et al, 2001; Wang et al, 2002; Li et al, 2004; Bauer et al, 2009, 2010; Boroujerdi et al, 2011)
The knockout mice showed a delayed development of mechanical hypersensitivity after partial sciatic nerve ligation (PSL) and loss of the analgesic effect of pregabalin (Patel et al, 2013)

Summary

Introduction

Gabapentinoids, such as pregabalin and gabapentin, are selective ligands for the a2d subunit of voltage-gated calcium channels (Li et al, 2011; Alexander et al, 2015). The 66th Annual Meeting of the American Academy of Neurology; 2014 April 26–May 3; Philadelphia, PA. Arakawa N, Yokoyama T, Domon Y, Matsuda, Inoue T, Kitano Y, Takahashi M, Yamamura N, and Kai K (2014) Pharmacological, pharmacokinetics and safety profiles of DS-5565, a novel a2d ligand. The 24th Annual Meeting of the Diabetic Neuropathy Study Group; 2014 Sept 12–14; Sopron, Hungary.

Methods

Results

Conclusion