Discovery of a Highly Selective Sigma-2 Receptor Ligand, 1-(4-(6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (CM398), with Drug-Like Properties and Antinociceptive Effects In Vivo.

The AAPS Journal
Sebastiano IntagliataChristopher R McCurdy

Abstract

The sigma-2 receptor has been cloned and identified as Tmem97, which is a transmembrane protein involved in intracellular Ca2+ regulation and cholesterol homeostasis. Since its discovery, the sigma-2 receptor has been an extremely controversial target, and many efforts have been made to elucidate the functional role of this receptor during physiological and pathological conditions. Recently, this receptor has been proposed as a potential target to treat neuropathic pain due to the ability of sigma-2 receptor agonists to relieve mechanical hyperalgesia in mice model of chronic pain. In the present work, we developed a highly selective sigma-2 receptor ligand (sigma-1/sigma-2 selectivity ratio > 1000), 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H- benzo[d]imidazol-2(3H)-one (CM398), with an encouraging in vitro and in vivo pharmacological profile in rodents. In particular, radioligand binding studies demonstrated that CM398 had preferential affinity for sigma-2 receptor compared with sigma-1 receptor and at least four other neurotransmitter receptors sites, including the norepinephrine transporter. Following oral administration, CM398 showed rapid absorption and peak plasma concentration (Cmax) occurred ...Continue Reading

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Citations

Nov 26, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kai YangTaolei Sun
Oct 14, 2020·European Journal of Medicinal Chemistry·Xiao-Yang XieYun-Sheng Huang
Jun 3, 2021·Journal of Medicinal Chemistry·Antonino N FallicaSebastiano Intagliata
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Giuseppe RomeoLoredana Salerno

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Methods Mentioned

BETA
pharmacotherapies
column chromatography
competition binding

Software Mentioned

ARRIVE
MassLynx
ChemDraw Ultra
Phoenix WinNonlin

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