ABSTRACT
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aß25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aß25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
Subject(s)
Aggression/drug effects , Alzheimer Disease/drug therapy , Cognitive Dysfunction/drug therapy , Glycogen Synthase Kinase 3/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Alzheimer Disease/complications , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Apoptosis/drug effects , Behavior, Animal/drug effects , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/pathology , Cognitive Dysfunction/etiology , Cognitive Dysfunction/pathology , Disease Models, Animal , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/pathology , Neuroprotective Agents/therapeutic use , Phosphorylation/drug effects , Primary Cell Culture , Rats , Spinal Cord/drug effects , Spinal Cord/pathology , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Anxiety Agents/pharmacology , Anxiety Disorders/drug therapy , Cannabinoid Receptor Agonists/metabolism , Carbamates/pharmacology , Dioxanes/pharmacology , Enzyme Inhibitors/pharmacology , Receptors, Cannabinoid/genetics , Stress, Psychological/drug therapy , Acute Disease , Amides , Amidohydrolases/genetics , Amidohydrolases/metabolism , Animals , Anti-Anxiety Agents/chemical synthesis , Anxiety Disorders/physiopathology , Arachidonic Acids/metabolism , Carbamates/chemical synthesis , Chronic Disease , Dioxanes/chemical synthesis , Endocannabinoids/metabolism , Enzyme Inhibitors/chemical synthesis , Ethanolamines/metabolism , Female , Gene Expression , Male , Mice , Oleic Acids/metabolism , Palmitic Acids/metabolism , Polyunsaturated Alkamides/metabolism , Rats, Sprague-Dawley , Receptors, Cannabinoid/metabolism , Stress, Psychological/physiopathologyABSTRACT
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
Pyridyl-substituted 1,3,5-triazines were synthesized in good to excellent yields via an unprecedented one-step cyclocondensation of 4H-pyrido[1,3]oxazin-4-ones with amidines at room temperature or under microwave irradiations. The broad applicability was demonstrated by 33 examples with a variety of amidines and three different 4H-pyrido[1,3]oxazin-4-one chemical series. In addition, a one-pot process from 4H-pyrido[1,3]oxazin-4-one precursors (imide sodium salts) was developed and led to the desired triazines compounds, thus allowing a one-step economy in their global synthetic preparation. This approach provides rapid access to pyridyl (or pyridone)-substituted 1,3,5-triazines with high potential in various fields of application.
Subject(s)
Oxazines/chemistry , Triazines/chemical synthesis , Cyclization , Molecular Structure , Triazines/chemistryABSTRACT
Unreported 2-substituted 4H-pyrido[e][1,3]oxazin-4-ones are synthesized via an unprecedented intramolecular O-arylation of N-aroyl- and N-heteroaroyl-(iso)nicotinamides under microwave irradiations, in good to excellent yields. The broad applicability was demonstrated by 24 examples with a variety of substituents at the 2-position of the final compounds and 3 possible positions for the nitrogen atom of the pyridine ring. In addition, transformation of one of these compounds into 2-hydroxypyridyl-substituted 1,2,4-triazole and 1,2,4-oxazinone was realized. This approach opens a rapid access to a new bicyclic heteroaromatic chemical series with high potential in medicinal chemistry.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Oxazines/chemistry , Pyridines/chemistry , Chemistry, Pharmaceutical , Structure-Activity RelationshipABSTRACT
Azabicyclo[2.2.1]heptane and -[3.3.1]nonane scaffolds (X = Cl, Br) containing a pyridinyl substituent at the bridgehead position were prepared via two complementary chemical pathways, either by the transformation of a methoxy group into a synthetically valuable chlorine atom at the C-6 position of the pyridine moiety or by means of a regioselective C-6 deprotonation/halogenation process of the pyridine moiety exemplified by chlorination or bromination. These newly generated scaffolds were then engaged in Suzuki-Miyaura coupling reactions to provide α7 nicotinic ligands. Both chemical series were evaluated in vitro for their affinity at α7 nicotinic receptors, revealing nanomolar potency with significant selectivity over the α4ß2 nicotinic subtype. These approaches offer a general access to these α7 nicotinic scaffolds and ligands.
Subject(s)
Alkanes/chemistry , Azabicyclo Compounds/chemical synthesis , Chemistry, Pharmaceutical/methods , Heptanes/chemistry , Nicotinic Agonists/chemical synthesis , Receptors, Nicotinic/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Azabicyclo Compounds/metabolism , Azabicyclo Compounds/pharmacology , Chlorides/chemistry , Halogenation , Humans , Ligands , Magnetic Resonance Spectroscopy , Nicotinic Agonists/metabolism , Nicotinic Agonists/pharmacology , Protons , Pyridines/chemistry , Schizophrenia/drug therapy , Schizophrenia/metabolism , Stereoisomerism , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4ß2 nicotinic subtype.
Subject(s)
Alkanes/chemical synthesis , Aza Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Heptanes/chemical synthesis , Nicotine/chemistry , Ligands , Molecular StructureABSTRACT
Variously substituted linear enediynes phosphines oxides possessing the double bond at either the terminal or internal position and with the phosphine oxide appended onto the alkyne or the alkene terminus have been prepared. Their cobalt(I)-mediated cyclizations produce the eta(4)-complexed tricyclic compounds in high yields. The endo/exo selectivity depends on both the position of the phosphine oxide on the enediyne and the position of the double bond in the tether. With chiral phosphine oxides, a certain degree of induction was observed, and depending on the substituents on the phosphorus atom, the diastereoselectivity can reach 74%. Up to now, it is the highest level reported for such a cyclization in which a stereogenic center is created. Regarding all of our results, two reaction pathways involving an initial coordination of the cobalt moiety on the chelating site of the substituent have been suggested to explain the observed selectivities.
