title: Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.
abstract: OBJECTIVE
  Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter-2 (GlyT2), there are also some reports of toxicity and their development was discontinued.
  
  
  METHODS
  In order to clarify the possibility of targeting GlyT2 for the treatment of pain, we have used an integrated approach comprising in vitro pharmacology, selectivity, bioavailability, in vivo efficacy and safety assessment to analyse the properties and efficacy of ALX-1393 and Org-25543, the two published GlyT2 inhibitors from which in vivo data are available.
  
  
  RESULTS
  We report that these compounds have a different set of undesirable properties that limit their usefulness as pharmacological tools. Importantly, we discover that inhibitors of GlyT2 can exert an apparent reversible or irreversible inhibition of the transporter and describe a new class of reversible GlyT2 inhibitors that preserves efficacy while avoiding acute toxicity.
  
  
  CONCLUSIONS
  Our pharmacological comparison of two closely related GlyT2 inhibitors with different modes of inhibition provides important insights into their safety and efficacy profiles, uncovering that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. These findings shed light into the drawbacks associated with the early GlyT2 inhibitors and describe a new mechanism that might serve as the starting point for new drug development.
authors: New Medicines, UCB, Braine-L'Alleud, Belgium.
authors: A
authors: A
authors: Mingorance-Le Meur
authors: P
authors: P
authors: Ghisdal
authors: B
authors: B
authors: Mullier
authors: P
authors: P
authors: De Ron
authors: P
authors: P
authors: Downey
authors: C
authors: C
authors: Van Der Perren
authors: V
authors: V
authors: Declercq
authors: S
authors: S
authors: Cornelis
authors: M
authors: M
authors: Famelart
authors: J
authors: J
authors: Van Asperen
authors: E
authors: E
authors: Jnoff
authors: J P
authors: JP
authors: Courade
mesh_terms: D000700:Analgesics / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000633:toxicity; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002199:Capillary Permeability; D002460:Cell Line; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D018684:Glycine Agents / Q000494:pharmacology* / Q000633:toxicity; D050487:Glycine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D012694:Serine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection; D014982:Xenopus laevis
chemical_list: C532849:4-benzyloxy-3,5-dimethoxy-N-(1-(dimethylaminocyclopently)methyl)benzamide; C539864:ALX 1393; D000700:Analgesics; D001549:Benzamides; D018684:Glycine Agents; D050487:Glycine Plasma Membrane Transport Proteins; C493271:SLC6A5 protein, human; C493270:Slc6a5 protein, mouse; D005557:Formaldehyde; D012694:Serine
keywords: glycine; neuropathic pain; pain; reversible inhibitor
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