The deuterated pyrazoloquinolinone targeting α6 subunit-containing GABAA receptor as novel candidate for inhibition of trigeminovascular system activation: implication for migraine therapy
Year: 2024
Type: article
Abstract: Introduction The α6 subunit-containing GABAA receptors (α6GABAARs) 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 α6GABAAR-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 α6GABAAR-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 α6GABAARs to inhibit TGVS activation, with relatively favourable pharmacokinetic properties.
Source: Frontiers in Pharmacology
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,295
Funders: National Science Foundation, Ministry of Higher Education, Malaysia, Ministry of Science and Technology, Taiwan, National Health Research Institutes, National Taiwan University Hospital, National Taiwan University, National Science and Technology Council, National Institutes of Health, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Division of Chemistry
Awards: G1041262985, G1970462610, G3332552677, G400706969, Drug Repurposing: Migraine Therapy by Positively Modulating Trigeminal Α6gaba-A Receptors, A Novel Therapy for Migraine: Alpha 6-Containing Gaba-A Receptor Positive Allosteric Modulators (Pyrazoloquinolinones and Hispidulin), MRI: Acquisition of a 500 MHz Nuclear Magnetic Resonance (NMR) Spectrometer to Enhance NMR Capabilities at a Major Urban Research Institution, G5640637314, G7125625774, G7337478357, G7653821823, G767927726, Synthesis of Alpha2/Alpha3 GABA Agonists to Treat Neuropathic Pain, G8424711855, G9000044875, G9000111134
OpenAlex ID: W4401889092