ABSTRACT
Lurasidone [(3aR,4S,7R,7aS)-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects.
Subject(s)
Antipsychotic Agents/pharmacology , Isoindoles/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Serotonin/metabolism , Thiazoles/pharmacology , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/therapeutic use , Anxiety/drug therapy , Anxiety/metabolism , Behavior, Animal/drug effects , CHO Cells , Cricetinae , Cricetulus , Cyclic AMP/metabolism , Dopamine/metabolism , Guinea Pigs , Humans , Hyperkinesis/drug therapy , Hyperkinesis/metabolism , Isoindoles/adverse effects , Isoindoles/therapeutic use , Ligands , Lurasidone Hydrochloride , Male , Mice , Mice, Inbred Strains , Molecular Structure , Protein Binding , Rats , Rats, Sprague-Dawley , Rats, Wistar , Receptor, Serotonin, 5-HT1A/genetics , Receptors, Serotonin/genetics , Thiazoles/adverse effects , Thiazoles/therapeutic use , Transfection , Tremor/drug therapy , Tremor/metabolismABSTRACT
A new peptaibol compound, SPF-5506-A4, was isolated from the fermentation broth of Trichoderma sp. SPF-5506. The chemical structure of the 14-residue peptide was determined by MS, NMR and amino acid sequence analyses. The absolute configuration of amino acid residues in the acid hydrolysate was determined by Marfey's method. The structure of SPF-5506-A4 was established as Ac-Aib-L-Asn-L-Ile-Aib-L-Pro-L-Ser-L-Ile-Aib-L-Pro-L-Leu-L-Leu-Aib-L-Pro-L-leucinol. The compound inhibited amyloid beta-peptide formation in primary guinea pig cerebral cortex neuron cell culture dose-dependently with an IC50 of 0.1 microg/ml. Cytotoxicity was not observed at concentrations of <3 microg/ml.
Subject(s)
Amyloid beta-Peptides/biosynthesis , Cerebral Cortex/drug effects , Neurons/drug effects , Oligopeptides/pharmacology , Peptides/chemistry , Peptides/metabolism , Trichoderma/metabolism , Amino Acid Sequence , Amyloid beta-Peptides/metabolism , Animals , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/metabolism , Fermentation , Guinea Pigs , Mass Spectrometry , Molecular Sequence Data , Neurons/metabolism , Oligopeptides/biosynthesis , Peptides/pharmacology , Trichoderma/classification , Trichoderma/growth & developmentABSTRACT
Two new human chymase inhibitors, SPF-32629A and B, were isolated from the cultured broth of Penicillium sp. SPF-32629. These structures were determined by spectroscopic methods and identified as new pyridone compounds. SPF-32629B was the carboxylated derivative of SPF-32629A. SPF-32629A and B specifically inhibited human chymase among four serine proteases tested with the IC50 of 0.25 and 0.42 microg/ml, respectively.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Niacin/analogs & derivatives , Penicillium/metabolism , Protease Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Serine Endopeptidases/metabolism , Antibiotics, Antineoplastic/biosynthesis , Cell Survival/drug effects , Chemical Phenomena , Chemistry, Physical , Chromatography, High Pressure Liquid , Chymases , Fermentation , HL-60 Cells , Humans , Magnetic Resonance Spectroscopy , Molecular Conformation , Niacin/chemistry , Penicillium/classification , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, UltravioletABSTRACT
Two new 24-membered macrolides, SPA-6952A and B, were isolated from the fermentation broth of Streptomyces sp. SPA-6952. The structures of the new macrolides were determined by spectral analyses, including 2D NMR techniques. These compounds exhibited cytotoxic activity against human promyelocytic leukemia HL-60 cells.
Subject(s)
Antibiotics, Antineoplastic/biosynthesis , Macrolides/metabolism , Streptomyces/metabolism , Antibiotics, Antineoplastic/isolation & purification , Antibiotics, Antineoplastic/pharmacology , Chromatography, High Pressure Liquid , Fermentation , HL-60 Cells , Humans , Macrolides/isolation & purification , Macrolides/pharmacology , Molecular Conformation , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared , Spectrophotometry, UltravioletABSTRACT
Seven new antimycin antibiotics, named antimycins A10, A11, A12, A13, A14, A15 and A16, were isolated from the fermentation broth of strains of Streptomyces spp. SPA-10191 and SPA-8893, along with known antimycins A1, A2, A3 and A4. The structures of the new antimycins were determined by spectral analyses, including 2D NMR techniques. These compounds exhibited antifungal activity against Candida utilis.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Antifungal Agents/isolation & purification , Antimycin A/analogs & derivatives , Streptomyces/classification , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/drug effects , Fermentation , Molecular Structure , Structure-Activity RelationshipABSTRACT
A new semaphorin inhibitor xanthofulvin was isolated from the cultured broth of a fungus Penicillium sp. SPF-3059 along with a known compound vinaxanthone by solvent extraction and bioassay-guided fractionation. The tautomeric structure of xanthofulvin was determined by spectroscopic analyses. The two compounds exhibited significant semaphorin inhibitory activity with IC50 values of 0.09 and 0.1 microg/ml, respectively, in semaphorin3A-induced growth cone collapse assay using cultured chick dorsal root ganglia neurons.
Subject(s)
Chromones , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Penicillium/metabolism , Semaphorin-3A/antagonists & inhibitors , Xanthenes/chemistry , Xanthones , Animals , Chick Embryo , Enzyme Inhibitors/isolation & purification , Fermentation , Ganglia, Spinal/drug effects , Ganglia, Spinal/enzymology , Growth Cones/metabolism , Microscopy, Electron, Scanning , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Penicillium/chemistry , Semaphorin-3A/metabolism , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Xanthenes/isolation & purification , Xanthenes/pharmacologyABSTRACT
SM-216289 (xanthofulvin) isolated from the fermentation broth of a fungal strain, Penicillium sp. SPF-3059, was identified as a strong semaphorin 3A (Sema3A) inhibitor. Sema3A-induced growth cone collapse of dorsal root ganglion neurons in vitro was completely abolished in the presence of SM-216289 at levels less than 2 mum (IC50 = 0.16 mum). When dorsal root ganglion explants were co-cultured with Sema3A-producing COS7 cells in a collagen gel matrix, SM-216289 enabled neurites to grow toward the COS7 cells. SM-216289 diminished the binding of Sema3A to its receptor neuropilin-1 in vitro, suggesting a direct interference of receptor-ligand association. Moreover, our data suggest that SM-216289 interacted with Sema3A directly and blocked the binding of Sema3A to its receptor. We examined the efficacy of SM-216289 in vivo using a rat olfactory nerve axotomy model, in which strong Sema3A induction has been reported around regenerating axons. The regeneration of olfactory nerves was significantly accelerated by a local administration of SM-216289 in the lesion site, suggesting the involvement of Sema3A in neural regeneration as an inhibitory factor. SM-216289 is an excellent molecular probe to investigate the function of Sema3A, in vitro and in vivo, and may be useful for the treatment of traumatic neural injuries.
Subject(s)
Chromones/pharmacology , Semaphorin-3A/antagonists & inhibitors , Xanthones/pharmacology , Animals , COS Cells , Cells, Cultured , Chick Embryo , Coculture Techniques , Collagen/metabolism , Dose-Response Relationship, Drug , Inhibitory Concentration 50 , Ligands , Mice , Models, Biological , Models, Chemical , Neurons/metabolism , Neurons/pathology , Olfactory Nerve/metabolism , Protein Binding , Rats , Rats, Wistar , Time FactorsABSTRACT
STO-609, a selective inhibitor of Ca(2+)/calmodulin-dependent protein kinase kinase (CaM-KK) was synthesized, and its inhibitory properties were investigated both in vitro and in vivo. STO-609 inhibits the activities of recombinant CaM-KK alpha and CaM-KK beta isoforms, with K(i) values of 80 and 15 ng/ml, respectively, and also inhibits their autophosphorylation activities. Comparison of the inhibitory potency of the compound against various protein kinases revealed that STO-609 is highly selective for CaM-KK without any significant effect on the downstream CaM kinases (CaM-KI and -IV), and the IC(50) value of the compound against CaM-KII is approximately 10 microg/ml. STO-609 inhibits constitutively active CaM-KK alpha (glutathione S-transferase (GST)-CaM-KK-(84-434)) as well as the wild-type enzyme. Kinetic analysis indicates that the compound is a competitive inhibitor of ATP. In transfected HeLa cells, STO-609 suppresses the Ca(2+)-induced activation of CaM-KIV in a dose-dependent manner. In agreement with this observation, the inhibitor significantly reduces the endogenous activity of CaM-KK in SH-SY5Y neuroblastoma cells at a concentration of 1 microg/ml (approximately 80% inhibitory rate). Taken together, these results indicate that STO-609 is a selective and cell-permeable inhibitor of CaM-KK and that it may be a useful tool for evaluating the physiological significance of the CaM-KK-mediated pathway in vivo as well as in vitro.
