Discovery and development of an oral analgesic targeting the α2B adrenoceptor
Abstract
Noradrenaline is a major monoaminergic neurotransmitter involved in pain modulation through an α2A-adrenergic receptor. Hence, α2-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(3 H )-ylidene)propan-2-one [adrenergic inducer of analgesia (ADRIANA)], a newly identified α2B subtype-specific antagonist, specifically promotes noradrenaline release in the murine spinal dorsal horn and produces analgesic effects by stimulating the α2A-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 α2B adrenoceptor showed normal responses to mechanical pain, but the analgesic effect of ADRIANA was not significantly detected. These findings reveal that the α2B adrenoceptor is a promising target for nonopioid analgesics through the activation of the α2A-dependent descending pathway.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Masayasu Toyomoto
Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University
Takashi Kurihara
Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University
Takayuki Nakagawa
Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University
Asuka Inoue
Ryo Kimura
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University
Isao Kii
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University
Teruo Sawada
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University
Takashi Ogihara
Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital
Kazuki Nagayasu
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University
Takayuki Kishi
Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University,
Hiroshi Onogi
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University
Dohyun Im
Department of Cell Biology, Graduate School of Medicine, Kyoto University
Hidetsugu Asada
Department of Cell Biology, Graduate School of Medicine, Kyoto University
So Iwata
Jumpei Taguchi
Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo
Yuto Sumida
Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo
Suguru Yoshida
Department of Energy and Hydrocarbon Chemistry
Junken Aoki
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo
Takamitsu Hosoya
Chemical Bioscience Team, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Chiyoda-ku, Tokyo 101-0062, Japan
Masatoshi Hagiwara
Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University