Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.

Background And Purpose: 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.

Drug binding assays do not reveal specific binding of lacosamide to collapsin response mediator protein 2 (CRMP-2).

Aims: Lacosamide (LCM; SPM 927, Vimpat®) is an antiepileptic drug (AED) used as adjunctive treatment for adults with partial-onset seizures. LCM has a different mode of action from traditional sodium channel blocking AEDs in that it selectively enhances slow inactivation of sodium channels without affecting fast inactivation. Initial investigations suggested that LCM might have an additional mode of action by binding to the collapsin response mediator protein 2 (CRMP-2), which is further investigated here.

Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194).

Competition experiments with [(3)H]mepyramine showed that cetirizine and its enantiomers, levocetirizine and (S)-cetirizine, bound with high affinity and stereoselectivity to human H(1) histamine receptors (K(i) values of 6, 3, and 100 nM, respectively). Cetirizine and levocetirizine were 600-fold more selective for H(1) receptors compared with a panel of receptors and channels. Binding results indicated that the interaction between cetirizine, its enantiomers, and histamine is compatible with a competitive behavior, in contrast with the noncompetitive profile of cetirizine and levocetirizine observed in isolated organs.