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

Abstract

Mirogabalin ([(1,5,6)-6-(aminomethyl)-3-ethylbicyclo[3.2.0]hept-3-en-6-yl]acetic acid), a novel ligand for the 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 ligand. Mirogabalin showed potent and selective binding affinities for the subunits, while having no effects on 186 off-target proteins. Similar to pregabalin, mirogabalin did not show clear subtype selectivity (-1 vs. -2) or species differences (human vs. rat). However, in contrast to pregabalin, mirogabalin showed greater binding affinities for human-1, human -2, rat-1, and rat -2 subunits; further, it had a slower dissociation rate for the-1 subunit than the -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 subunits, and slower dissociation rates for the -1 subunit than the-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.

Long‐term safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain

“…Mirogabalin has potent and selective binding affinities for human and rat α 2 δ subunits, and a slower dissociation rate for the α 2 δ‐1 versus α 2 δ‐2 subunit. It shows potent and long‐lasting analgesic effects in rat models for neuropathic pain and a wider safety margin for CNS side‐effects.…”

“…Mirogabalin has potent and selective binding affinities for human and rat α 2 δ subunits, and a slower dissociation rate for the α 2 δ‐1 versus α 2 δ‐2 subunit. It shows potent and long‐lasting analgesic effects in rat models for neuropathic pain and a wider safety margin for CNS side‐effects. In the preceding double‐blind phase III trial in Asian patients with DPNP, mirogabalin 15–30 mg/day was well tolerated and relieved DPNP in a dose‐dependent manner for up to 14 weeks.…”

“…It has higher binding affinities for α 2 δ‐1 and α 2 δ‐2 subunits than pregabalin, and a slower dissociation rate for α 2 δ‐1 than α 2 δ‐2. Additionally, mirogabalin showed more potent and longer lasting analgesic effects in experimental models of neuropathic pain in rats (partial sciatic nerve ligation and streptozotocin‐induced diabetic neuropathic pain). Furthermore, mirogabalin (10, 30 and 100 mg/kg) and pregabalin (30, 100 and 300 mg/kg) inhibited rotarod performance and locomotor activity in rats; however, the safety indices of mirogabalin were superior to those of pregabalin.…”

“…Mirogabalin is a novel, selective oral ligand of the α 2 δ calcium channel subunit. It has higher binding affinities for α 2 δ‐1 and α 2 δ‐2 subunits than pregabalin, and a slower dissociation rate for α 2 δ‐1 than α 2 δ‐2. Additionally, mirogabalin showed more potent and longer lasting analgesic effects in experimental models of neuropathic pain in rats (partial sciatic nerve ligation and streptozotocin‐induced diabetic neuropathic pain).…”

Mirogabalin for the treatment of diabetic peripheral neuropathic pain: A randomized, double‐blind, placebo‐controlled phase III study in Asian patients

“…The α 2 δ‐1 subunit of voltage‐dependent Ca 2+ channels in the nervous system is the main target for the analgesic effect of α 2 δ ligands, such as pregabalin. Although mirogabalin has a similar binding affinity for α 2 δ‐1 and α 2 δ‐2 subunits compared with pregabalin, mirogabalin shows slower dissociation rates from α 2 δ‐1 than α 2 δ‐2 and, in particular, a slower dissociation rate from α 2 δ‐1 relative to pregabalin. In a phase II study at sites in the USA, mirogabalin showed efficacy in reducing pain and associated sleep interference in patients with DPNP.…”