Discovery and development of an oral analgesic targeting the α2B adrenoceptor

Masayasu Toyomoto^{1

2

3

4}, Takashi Kurihara⁵, Takayuki Nakagawa^{6

7}, Asuka Inoue^{8

9}, Ryo Kimura^{1

10}, Isao Kii^{1

11}, Teruo Sawada^{1

4

12}, Takashi Ogihara^{7

13

14}, Kazuki Nagayasu⁹, Takayuki Kishi⁸, Hiroshi Onogi^{1

15}, Dohyun Im¹⁶, Hidetsugu Asada¹⁶, So Iwata¹⁶, Jumpei Taguchi¹⁷, Yuto Sumida¹⁷, Suguru Yoshida^{17

18}, Junken Aoki¹⁹, Takamitsu Hosoya¹⁷, Masatoshi Hagiwara^{1

4}

Affiliations

¹ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
² Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
³ Department of Drug Discovery for Intractable Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁴ Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁵ Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
⁶ Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan.
⁷ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto 606-8507, Japan.
⁸ Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan.
⁹ Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
¹⁰ Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan.
¹¹ Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, Nagano 399-4598, Japan.
¹² BTB Therapeutics, Inc., Escondido, CA 92026.
¹³ Department of Pharmacy, Kobe University Hospital, Hyogo 650-0017, Japan.
¹⁴ Center for Development of Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
¹⁵ KinoPharma, Inc., Tokyo 103-0023, Japan.
¹⁶ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
¹⁷ Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo 101-0062, Japan.
¹⁸ Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan.
¹⁹ Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.

PMID: 40773228
PMCID: PMC12358833 (available on 2026-02-07)
DOI: 10.1073/pnas.2500006122

Discovery and development of an oral analgesic targeting the α2B adrenoceptor

Masayasu Toyomoto et al. Proc Natl Acad Sci U S A. 2025.

. 2025 Aug 12;122(32):e2500006122.

doi: 10.1073/pnas.2500006122. Epub 2025 Aug 7.

Authors

Affiliations

¹ Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
² Department of Drug Discovery for Lung Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
³ Department of Drug Discovery for Intractable Diseases, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁴ Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
⁵ Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
⁶ Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan.
⁷ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto 606-8507, Japan.
⁸ Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi 980-8578, Japan.
⁹ Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
¹⁰ Department of Child Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan.
¹¹ Laboratory for Drug Target Research, Department of Agriculture, Graduate School of Science and Technology, Shinshu University, Nagano 399-4598, Japan.
¹² BTB Therapeutics, Inc., Escondido, CA 92026.
¹³ Department of Pharmacy, Kobe University Hospital, Hyogo 650-0017, Japan.
¹⁴ Center for Development of Integrative Education in Pharmacy and Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
¹⁵ KinoPharma, Inc., Tokyo 103-0023, Japan.
¹⁶ Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
¹⁷ Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, Tokyo 101-0062, Japan.
¹⁸ Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Tokyo 125-8585, Japan.
¹⁹ Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.

PMID: 40773228
PMCID: PMC12358833 (available on 2026-02-07)
DOI: 10.1073/pnas.2500006122

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(3H)-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.

Keywords: G-protein-coupled receptor; adrenergic antagonist; analgesic; noradrenaline; α2B-adrenergic receptor.

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Conflict of interest statement

Competing interests statement:M.T. is a scientific adviser, and T.S. is a founder and shareholder of BTB Therapeutics, Inc. M.H. is a founder, shareholder, Chief Strategy Officer and Chair of the Scientific Advisory Board of BTB Therapeutics, Inc. M.T., T. Kurihara, I.K., S.Y., T.H., and M.H. have filed patents related to ADRIANA. The other authors declare noconflicts of interest.

References

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Discovery and development of an oral analgesic targeting the α2B adrenoceptor

Affiliations

Discovery and development of an oral analgesic targeting the α2B adrenoceptor

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources