Discovery and development of an oral analgesic targeting the α2B adrenoceptor

• 成果类型: Article
• 署名作者: Toyomoto, Masayasu; Kurihara, Takashi; Nakagawa, Takayuki; Inoue, Asuka; Kimura, Ryo; Kii, Isao; Sawada, Teruo; Ogihara, Takashi; Nagayasu, Kazuki; Kishi, Takayuki; Onogi, Hiroshi; Im, Dohyun; Asada, Hidetsugu; Iwata, So; Taguchi, Jumpei; Sumida, Yuto; Yoshida, Suguru; Aoki, Junken; Hosoya, Takamitsu; Hagiwara, Masatoshi
• 署名单位: Kyoto University; Kyoto University; Kyoto University; Kyoto University; Kagoshima University; Wakayama Medical University; Kyoto University; Tohoku University; Kyoto University; University of Osaka; Shinshu University; Kobe University; Kyoto University; Kyoto University; Institute of Science Tokyo; Tokyo University of Science; University of Tokyo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10081
• DOI: 10.1073/pnas.2500006122
• 发表日期: 2025-08-12
• 关键词: alpha(2)-adrenergic receptor subtypes; conditioned place preference; spinal-cord; catecholamine release; noradrenaline release; nerve injury; nitric-oxide; opioid use; pain; brain

摘要

Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an alpha 2A-adrenergic receptor. Hence, alpha 2-adrenergic agonists such as clonidine and dexmedetomidine exhibit analgesic and opioid-sparing effects. However, their use is restricted to hospital settings due to potential risks of acute hypertension/ hypotension and bradycardia. Here, we report that (Z)-1-(3-ethyl-5-fluorobenzo[d] thiazol-2(3H)-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified alpha 2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the alpha 2A-dependent pain inhibitory pathway. Orally administered ADRIANA has potent analgesic effects in several nociceptive pain models of mice and nonhuman primates without cardiovascular effects. Mice with genetic loss of the alpha 2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the alpha 2B adrenoceptor is a promising target for nonopioid analgesics through the activation of the alpha 2A-dependent descending pathway.