title: Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile.
abstract: OBJECTIVE
  The GABA(B) receptor agonist, baclofen, has shown promising effects in patients suffering from pain, post-traumatic stress disorder, alcoholism, overactive bladder and gastroesophageal reflux disease. However, baclofen's short duration of action and side effects limit its wider use. Here we characterized a novel, GABA(B) receptor positive allosteric modulator (PAM) ADX71943.
  
  
  METHODS
  In vitro, ADX71943 was assessed for pharmacological activity and selectivity using recombinant and native GABA(B) receptors. In vivo ADX71943 was assessed in the acetic acid-induced writhing (AAW) test in mice and formalin tests (FTs) in mice and rats. Marble burying (MB) and elevated plus maze (EPM) tests, rotarod, spontaneous locomotor activity (sLMA) and body temperature (BT) tests in mice and rats were used to investigate centrally-mediated effects.
  
  
  RESULTS
  In vitro, in the presence of GABA, ADX71943 increased the potency and efficacy of agonists and showed selectivity at the GABA(B) receptor. ADX71943 reduced pain-associated behaviours in AAW; an effect blocked by GABA(B) receptor antagonist CGP63360. ADX71943 reduced pain in the FT in mice and rats, but was inactive in the MB and EPM despite reaching high concentrations in plasma. ADX71943 had no effect on BT, rotarod and sLMA.
  
  
  CONCLUSIONS
  ADX71943 showed consistent and target-related efficacy in tests of disorders that have a significant peripheral component (acute and chronic pain), while having no effect in those associated with centrally-mediated anxiety-like reactivity and side effects. Thus, ADX71943 is a useful pharmacological tool for delineation of peripherally- versus centrally-mediated effects of GABA(B) receptor activation.
authors.affiliation: Addex Therapeutics SA, Geneva, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Kalinichev
authors.forename: T
authors.initials: T
authors.lastname: Donovan-Rodriguez
authors.forename: F
authors.initials: F
authors.lastname: Girard
authors.forename: E
authors.initials: E
authors.lastname: Riguet
authors.forename: M
authors.initials: M
authors.lastname: Rouillier
authors.forename: B
authors.initials: B
authors.lastname: Bournique
authors.forename: H
authors.initials: H
authors.lastname: Haddouk
authors.forename: V
authors.initials: V
authors.lastname: Mutel
authors.forename: S
authors.initials: S
authors.lastname: Poli
mesh_terms: D019342:Acetic Acid; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D018757:GABA Modulators / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000235:genetics / Q000502:physiology*
chemical_list: D018757:GABA Modulators; D018080:Receptors, GABA-B; D019342:Acetic Acid; D002118:Calcium