title: The drug candidate, ADX71441, is a novel, potent and selective positive allosteric modulator of the GABABreceptor with a potential for treatment of anxiety, pain and spasticity.
abstract: Positive allosteric modulation of the GABABreceptor is a promising alternative to direct activation of the receptor as a therapeutic approach for treatment of addiction, chronic pain, anxiety, epilepsy, autism, Fragile X syndrome, and psychosis. Here we describe in vitro and in vivo characterization of a novel, potent and selective GABABpositive allosteric modulator (PAM) N-(5-(4-(4-chloro-3-fluorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)-2-fluorophenyl)acetamide (ADX71441). In vitro, Schild plot and reversibility tests at the target confirmed PAM properties of the compound. In mice and rats ADX71441 is bioavailable after oral administration and is brain penetrant. A single dose of ADX71441 had an anxiolytic-like profile in the mouse marble burying test (minimum effective dose; MED 3 mg/kg) as well as in the elevated plus maze test in mice and rats (both MED 3 mg/kg). Also, in mice, acute administration of ADX71441 reduced visceral pain-associated behaviors in the acetic acid-induced writhing test. ADX71441 dose-dependently reduced time on rotarod in rats (MED 10 mg/kg) indicative of muscle-relaxant qualities. ADX71441 reduced locomotor activity in mice (10 mg/kg) and rats (3 mg/kg) after single dose; however, following sub-chronic administration in mice, 30 mg/kg ADX71441 was associated with normal locomotor activity. While acute administration of ADX71441 reduced body temperature in rats and mice (both MED 10 mg/kg), the effect in the former was transient, rapidly returning to normal levels despite high concentrations of the compound remaining in plasma. Thus, the GABABPAM ADX71441 represents a valid therapeutic approach for development of novel treatment of anxiety, pain and spasticity.
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: Françoise
authors.initials: F
authors.lastname: Girard
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Hasnaà
authors.initials: H
authors.lastname: Haddouk
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Rouillier
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Riguet
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: Vincent
authors.initials: V
authors.lastname: Mutel
authors.affiliation: Addex Therapeutics SA, Chemin des Mines 9, CH-1202, Geneva, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Lütjens
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; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009128:Muscle Spasticity / Q000188:drug therapy*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000187:drug effects* / Q000378:metabolism; D045442:Rotarod Performance Test; D014157:Transcription Factors / Q000494:pharmacology* / Q000627:therapeutic use; D014227:Triazines
chemical_list: C000592313:ADX71441; D000081:Acetamides; D000700:Analgesics; D014151:Anti-Anxiety Agents; D001426:Bacterial Proteins; D018080:Receptors, GABA-B; D014157:Transcription Factors; D014227:Triazines; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: Allosteric modulator; Anxiety; Baclofen; Body temperature; Clinical candidate; GABA; Pain; Spasticity