Pharmacological Properties of DOV 315,090, an ocinaplon metabolite

metabolit

Mechanisms of GABAA and GABAB Receptor Gene Regulation and Cell Surface Expression

The γ-aminobutyric acid (GABA) neurotransmitter acting through ionotropic and metabotropic receptor classes exerts the major inhibitory control in the central nervous system. Therapeutic agents targeting GABA receptors (GABA-R), such as benzodiazepines and baclofen, are used to treat many nervous system conditions, including anxiety and spasticity. The subunit composition of GABA-Rs at the cell surface plays a critical role in determining their physiological and pharmacological properties, and alteration of GABA-R subunit expression has been associated with a number of diseases including schizophrenia, temporal lobe epilepsy, and alcoholism. The ionotropic type A GABA receptor (GABAAR) and type C GABA receptor (GABACR) are pentameric complexes that comprise a ligand gated chloride channel. The metabotropic type B GABA receptor (GABABR) is a heterodimer that couples G protein-signaling to GABA binding. There are eight classes of ionotropic receptor subunits and only two metabotropic receptor subunit classes. Most of the GABAAR subunit genes are localized in syntenic β-α-γ gene clusters on four chromosomes but the two GABABR genes are localized on distinct chromosomes. Control over subunit expression in different brain regions and during development is orchestrated at the genomic level by the use of multiple promoter regions and through the alternative splicing of GABA-R subunit RNAs. This chapter examines current GABA-R research relevant to the many levels of control over receptor gene regulation and cell surface receptor expression that may be relevant to both health and disease.Fil: Farb, David Howard. No especifíca;Fil: Steiger, Janine L.. No especifíca;Fil: Martinez, Stella Maris. No especifíca;Fil: Gravielle, Maria Clara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Gibbs, Terrell T.. No especifíca;Fil: Russek, Shelley J.. No especifíca

Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids

1. The neurosteroid pregnenolone sulphate (PS) potentiates N-methyl-D-aspartate (NMDA) receptor mediated responses in various neuronal preparations. The NR1 subunit can combine with NR2A, NR2B, NR2C, or NR2D subunits to form functional receptors. Differential NR2 subunit expression in brain and during development raises the question of how the NR2 subunit influences NMDA receptor modulation by neuroactive steroids. 2. We examined the effects of PS on the four diheteromeric NMDA receptor subtypes generated by co-expressing the NR1(100) subunit with each of the four NR2 subunits in Xenopus oocytes. Whereas PS potentiated NMDA-, glutamate-, and glycine-induced currents of NR1/NR2A and NR1/NR2B receptors, it was inhibitory at NR1/NR2C and NR1/NR2D receptors. 3. In contrast, pregnanolone sulphate (3α5βS), a negative modulator of the NMDA receptor that acts at a distinct site from PS, inhibited all four subtypes, but was approximately 4 fold more potent at NR1/NR2C and NR1/NR2D than at NR1/NR2A and NR1/NR2B receptors. 4. These findings demonstrate that residues on the NR2 subunit are key determinants of modulation by PS and 3α5βS. The modulatory effects of PS, but not 3α5βS, on dose-response curves for NMDA, glutamate, and glycine are consistent with a two-state model in which PS either stabilizes or destabilizes the active state of the receptor, depending upon which NR2 subunit is present. 5. The selectivity of sulphated steroid modulators for NMDA receptors of specific subunit composition is consistent with a neuromodulatory role for endogenous sulphated steroids. The results indicate that it may be possible to develop therapeutic agents that target steroid modulatory sites of specific NMDA receptor subtypes