Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile.

Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin.

Selective inhibition of extra-synaptic α5-GABA receptors by S44819, a new therapeutic agent.

In the mammalian central nervous system (CNS) GABA receptors (GABARs) mediate neuronal inhibition and are important therapeutic targets. GABARs are composed of 5 subunits, drawn from 19 proteins, underpinning expression of 20-30 GABAR subtypes. In the CNS these isoforms are heterogeneously expressed and exhibit distinct physiological and pharmacological properties.

Behavioural pharmacology of the α5-GABA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models.

Previous work has shown that S44819 is a novel GABAA receptor (GABAR) antagonist, which is selective for extrasynaptic GABARs incorporating the α5 subunit (α5-GABARs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.

Loop-F of the α-subunit determines the pharmacologic profile of novel competitive inhibitors of GABA receptors.

The neurotransmitter γ-amino butyric acid (GABA) has a fundamental role in CNS function and ionotropic (GABA) receptors that mediate many of the actions of GABA are important therapeutic targets. This study reports the mechanism of action of novel GABA antagonists based on a tricyclic oxazolo-2,3-benzodiazepine scaffold. These compounds are orthosteric antagonists of GABA on heteropentameric GABA receptors of αxβ2γ2 configuration expressed in HEK293 cells.

A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential.

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABAA receptors containing the alpha 5 subunit (GABAA α5), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABAA α5 receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3]benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test.