The deuterated pyrazoloquinolinone targeting α6 subunit-containing GABAA receptor as novel candidate for inhibition of trigeminovascular system activation: implication for migraine therapy

Pi-Chuan Fan; Lih-Chu Chiou; Tzu-Hsuan Lai; Dishary Sharmin; James Cook; Ming Tatt Lee

doi:10.3389/fphar.2024.1451634

The deuterated pyrazoloquinolinone targeting α6 subunit-containing GABA_A receptor as novel candidate for inhibition of trigeminovascular system activation: implication for migraine therapy

Front Pharmacol. 2024 Aug 26:15:1451634. doi: 10.3389/fphar.2024.1451634. eCollection 2024.

Authors

Pi-Chuan Fan^{1

2

3}, Lih-Chu Chiou^{3

4

5

6}, Tzu-Hsuan Lai², Dishary Sharmin⁷, James Cook⁷, Ming Tatt Lee^{4

8

9}

Affiliations

¹ Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
³ Clinical Center for Neuroscience and Behavior, National Taiwan University Hospital, Taipei, Taiwan.
⁴ Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁵ Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, Taiwan.
⁶ Graduate Institute of Acupuncture Sciences, China Medical University, Taichung, Taiwan.
⁷ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, United States.
⁸ Faculty of Pharmaceutical Sciences, UCSI University, Kuala Lumpur, Malaysia.
⁹ UCSI Wellbeing Research Centre, UCSI University, Kuala Lumpur, Malaysia.

Abstract

Introduction: The α6 subunit-containing GABA_A receptors (α6GABA_ARs) are highly expressed in the trigeminal ganglia (TG), the sensory hub of the trigeminovascular system (TGVS). Hypo-GABAergic transmission in the TG was reported to contribute to migraine-related behavioral and histopathological phenotypes. Previously, we found that Compound 6, an α6GABA_AR-selective positive allosteric modulator (PAM), significantly alleviated TGVS activation-induced peripheral and central sensitization in a capsaicin-induced migraine-mimicking model.

Methods: Here, we tested whether the deuterated analogues of Compound 6, namely DK-1-56-1 and RV-I-29, known to have longer half-lives than the parent compound, can exert a similar therapeutic effect in the same model. The activation of TGVS was triggered by intra-cisternal (i.c.) instillation of capsaicin in male Wistar rats. Centrally, i.c. capsaicin increased the quantity of c-Fos-immunoreactive (c-Fos-ir) neurons in the trigeminal cervical complex (TCC). Peripherally, it increased the calcitonin gene-related peptide immunoreactivity (CGRP-ir) in TG, and caused CGRP release, leading to CGRP depletion in the dura mater.

Results: DK-I-56-1 and RV-I-29, administered intraperitoneally (i.p.), significantly ameliorated the TCC neuronal activation, TG CGRP-ir elevation, and dural CGRP depletion induced by capsaicin, with DK-I-56-1 demonstrating better efficacy. The therapeutic effects of 3 mg/kg DK-I-56-1 are comparable to that of 30 mg/kg topiramate. Notably, i.p. administered furosemide, a blood-brain-barrier impermeable α6GABA_AR-selective antagonist, prevented the effects of DK-I-56-1 and RV-I-29. Lastly, orally administered DK-I-56-1 has a similar pharmacological effect.

Discussion: These results suggest that DK-I-56-1 is a promising candidate for novel migraine pharmacotherapy, through positively modulating TG α6GABA_ARs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.

Keywords: GABA; positive allosteric modulator; pyrazoloquinolinone; trigeminal ganglia; trigeminovascular system; α6GABAAR.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was supported by the grants from the Ministry of Science and Technology/National Science and Technology Council, Taiwan (MOST 106-2314-B-002-195 and MOST 107-2314-B-002-170 to P-CF; MOST 108-2320-B-002-029-MY3, NSTC111-2321-B-002-045 and NSTC112-2321-B-002-059 to L-CC), National Taiwan University Hospital, Taiwan (NTUH 108-S4184 and NTUH 110-S4878 to P-CF), E-da Hospital, Taiwan (106-EDN20 and 108-EDN08 to P-CF), the National Health Research Institutes, Taiwan (NHRI-EX113-11114NI to L-CC), Ministry of Education, Taiwan (107M4022-3 to L-CC), National Institutes of Health, USA (R01NS076517 and R01MH096463 to JC), National Science Foundation, USA, Division of Chemistry (CHE-1625735 to JC), Ministry of Higher Education, Malaysia (FRGS/1/2021/SKK06/UCSI/02/4 and FRGS/1/2021/WAB13/UCSI/02/1 to ML) and UCSI University Research Excellence and Innovation Grant, Malaysia (REIG-FPS-2023/043 to ML).