title: ADX71943 and ADX71441, novel positive allosteric modulators of the GABABreceptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat.
abstract: We tested novel positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB), ADX71943 and ADX71441in the monosodium iodoacetate model of chronic osteoarthritis pain in rats with the objective to delineate the role of peripheral versus central GABABreceptor populations in modulation of chronic pain. Anesthetized Sprague-Dawley rats received an injection of monosodium iodoacetate into the knee and were tested for hyperalgesia starting post-MIA day 14. Effects of compounds on ipsilateral joint compression threshold were evaluated on post-MIA day 14 (after acute treatment), as well as after repeated, daily treatment on days 21 and 28 (ADX71943 only) and were compared to those of celecoxib (30mg/kg, p.o.). The PAMs were also tested in the rat rotarod test for potential muscle-relaxant effects. Acutely, ADX71943 (1-30mg/kg, p.o.), the peripherally restricted PAM, resulted in similar increases in pain threshold across the doses on day 14, while showing reduced efficacy on day 21 and no efficacy on day 28. A clear reduction in the efficacy of celecoxib across testing was also noted in this experiment. Acutely ADX71441 (0.3-15mg/kg, p.o.), the central-peripheral PAM, resulted in over 2-fold increases in pain threshold at 15mg/kg (but not at lower doses) on day 14, while causing more modest effects on day 21. Celecoxib increased pain threshold after both acute and daily treatment, showing overall similar efficacy. Thus, early, presumably more inflammatory phase of osteoarthritis pain in more sensitive to GABABPAMs with peripherally restricted profile, while later, presumably more neuropathic phase is more sensitive to PAMs with central-peripheral profile.
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland. Electronic address: mikhail.kalinichev@ipsen.com.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kalinichev
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Tansy
authors.initials: T
authors.lastname: Donovan-Rodriguez
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Françoise
authors.initials: F
authors.lastname: Girard
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Hasnaá
authors.initials: H
authors.lastname: Haddouk
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royer-Urios
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Huntingdon Life Sciences Ltd., Huntingdon Research Centre, Woolley Road Alconbury, Huntingdon PE28 4HS, UK.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Bate
authors.affiliation: Algos Preclinical Serves Inc., 2848 Patton Road, Roseville, MN 55113, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Marker
authors.affiliation: Algos Preclinical Serves Inc., 2848 Patton Road, Roseville, MN 55113, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Pomonis
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Poli
mesh_terms: D000081:Acetamides; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D059350:Chronic Pain / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007461:Iodoacetates / Q000494:pharmacology*; D008297:Male; D010003:Osteoarthritis / Q000150:complications*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000378:metabolism*; D045442:Rotarod Performance Test; D014157:Transcription Factors / Q000494:pharmacology* / Q000627:therapeutic use; D014227:Triazines
chemical_list: C000592313:ADX71441; C000617693:ADX71943; D000081:Acetamides; D001426:Bacterial Proteins; D007461:Iodoacetates; D018080:Receptors, GABA-B; D014157:Transcription Factors; D014227:Triazines
keywords: ADX71441; ADX71943; Allosteric modulation; Chronic pain; GABA; GABA(B); Inflammatory pain; Neuropathic pain; Osteoarthritis