ABSTRACT
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
Subject(s)
Attention/drug effects , Cognition Disorders/drug therapy , Cognition/drug effects , Indans/pharmacology , Memory/drug effects , Oxazoles/pharmacology , Pyrimidines/pharmacology , Receptors, AMPA/chemistry , Schizophrenia/drug therapy , Allosteric Site , Amphetamines/pharmacology , Animals , Calcium/metabolism , Cerebral Cortex/metabolism , Cyclic AMP/metabolism , Dizocilpine Maleate/chemistry , Dizocilpine Maleate/pharmacology , Electroconvulsive Therapy , HEK293 Cells , Humans , Indans/therapeutic use , Male , Maze Learning , Memory, Short-Term/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oxazoles/therapeutic use , Phenotype , Pyrimidines/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
Inducible nitric oxide synthase (iNOS) has been implicated in various central and peripheral pathophysiological diseases. Our high throughput screening initially identified a weak inhibitor of iNOS, thiocoumarin 13. From this lead, a number of potent derivatives were prepared that demonstrate favorable potency, selectivity and kinetics. Compound 30 has an IC50 of 60 nM for mouse iNOS and 185-fold and 9-fold selectivity for bovine eNOS and rat nNOS, respectively. In cellular assays for iNOS, this compound has micromolar potency. Furthermore, two compounds (16 and 30) demonstrate a reasonable pharmacokinetic profile in rodents. The synthesis, SAR, and biological activity of this novel class of compounds is described.
