ABSTRACT
Ubiquitin proteasome-mediated protein degradation has been implicated in posttranslational oncogenesis in medulloblastoma. Current research is evaluating the clinical implications of proteasome inhibition as a therapeutic target. In medulloblastoma cell lines, proteasome inhibitors induce apoptosis and inhibit cell proliferation via multiple pathways involving activation of caspase pathways, NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway inhibition, reduced AKT/mTOR pathway activity, and pro-apoptotic protein expression. Second-generation proteasome inhibitors demonstrate blood-brain barrier penetration while maintaining antitumor effect. This review summarizes the ubiquitin-proteasome system in the pathogenesis of medulloblastoma and the potential clinical implications.
Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Proteasome Inhibitors , Apoptosis , Cerebellar Neoplasms/drug therapy , Humans , Medulloblastoma/drug therapy , Proteasome Endopeptidase Complex , Proteasome Inhibitors/therapeutic use , UbiquitinABSTRACT
Antagonism of the histamine-H(3) receptor is one tactic being explored to increase wakefulness for the treatment of disorders such as excessive daytime sleepiness (EDS) as well as other sleep or cognitive disorders. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were shown to be potent and selective antagonists of the H(3) receptor. Several of these compounds demonstrated in vivo activity in a rat model of (R)-alpha-methyl histamine (RAMH) induced dipsogenia, and one compound (4e) provided an increase in wakefulness in rats as measured by polysomnographic methods. However, more detailed analysis of the PK/PD relationship suggested the presence of a common active metabolite which may preclude this series of compounds from further development.
Subject(s)
Biphenyl Compounds/chemistry , Drug Design , Drug Inverse Agonism , Histamine Antagonists/chemistry , Histamine Antagonists/pharmacology , Receptors, Histamine H3/metabolism , Sulfonamides/chemistry , Sulfonamides/pharmacology , Administration, Oral , Animals , Histamine Antagonists/administration & dosage , Histamine Antagonists/pharmacokinetics , Humans , Male , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thirst/drug effects , Wakefulness/drug effectsABSTRACT
A new series of H(3) antagonists derived from the natural product Conessine are presented. Several compounds from these new series retain the potency and selectivity of earlier diamine based analogs while exhibiting improved PK characteristics. One compound (3u) demonstrated functional antagonism of the H(3) receptor in an in vivo pharmacological model.
Subject(s)
Alkaloids/pharmacokinetics , Chemistry, Pharmaceutical/methods , Histamine Antagonists/pharmacology , Receptors, Histamine H3/chemistry , Animals , Binding, Competitive/drug effects , Central Nervous System/drug effects , Drug Design , Histamine Antagonists/chemistry , Kinetics , Models, Chemical , Molecular Structure , Rats , Structure-Activity RelationshipABSTRACT
A new family of Histamine H(3) receptor antagonists (5a-t) has been prepared based on the structure of the natural product Conessine, a known H(3) antagonist. Several members of the new series are highly potent and selective binders of rat and human H(3) receptors and display inverse agonism at the human H(3) receptor. Compound 5n exhibited promising rat pharmacokinetic properties and demonstrated functional antagonism of the H(3) receptor in an in-vivo pharmacological model.
