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1.
Biosci Biotechnol Biochem ; 88(6): 601-607, 2024 May 22.
Article in English | MEDLINE | ID: mdl-38569654

ABSTRACT

Lipoic acid trisulfide, a sulfane sulfur-containing trisulfide of α-lipoic acid, holds promise in pharmaceuticals, yet knowledge gaps persist regarding its synthesis, properties, and stability. Here, we synthesized the lipoic acid trisulfide with a purity exceeding 99% from α-lipoic acid on a gram scale and obtained novel ß-cyclodextrin clathrates (84%-95% yield). Differential scanning calorimetry confirmed the inclusion of lipoic acid trisulfide in ß-cyclodextrins. The resulting ß-cyclodextrin clathrates exhibited significant improvements in water solubility and thermal stability. This pioneering study demonstrated a novel approach to the practical preparation of trisulfide and its ß-cyclodextrin clathrates as active ingredients, paving the way for clinical development.


Subject(s)
Solubility , Thioctic Acid , beta-Cyclodextrins , Thioctic Acid/chemistry , beta-Cyclodextrins/chemistry , Sulfides/chemistry , Calorimetry, Differential Scanning , Drug Stability , Water/chemistry
2.
Chem Pharm Bull (Tokyo) ; 72(3): 303-308, 2024.
Article in English | MEDLINE | ID: mdl-38479853

ABSTRACT

Amine-free phosphorylation of various alcohols was developed with 4-methylpyridine N-oxide in the presence of 4 Å molecular sieves at room temperature. This mild method gave various phosphorylated products in high yield and could be applied to acid- or base-sensitive substrates. Furthermore, this method was also effective for the chemoselective phosphorylation of diols or polyols.


Subject(s)
Alcohols , Oxides , Picolines , Amines , Phosphorylation , Catalysis
4.
Article in English | MEDLINE | ID: mdl-37874338

ABSTRACT

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic- and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice 24 h post-treatment. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than anxiolytic effects.

5.
Res Sq ; 2023 Jul 07.
Article in English | MEDLINE | ID: mdl-37461593

ABSTRACT

Serotonergic psychedelics such as psilocybin, lysergic acid diethylamide, and DOI exert a hallucinatory effect through serotonin 5-HT 2A receptor (5-HT2A) activation. Recent studies have revealed that serotonergic psychedelics have therapeutic potential for neuropsychiatric disorders, including major depressive and anxiety-related disorders. However, the involvement of 5-HT2A in mediating the therapeutic effects of these drugs remains unclear. In this study, we ethopharmacologically analyzed the role of 5-HT2A in the occurrence of anxiolytic-and antidepressant-like effects of serotonergic psychedelics such as psilocin, an active metabolite of psilocybin, DOI, and TCB-2 in mice. Mice with acute intraperitoneal psychedelic treatment exhibited significantly shorter immobility times in the forced swimming test (FST) and tail-suspension test (TST) than vehicle-treated control mice 24 h post-treatment. These effects were eliminated by pretreatment with volinanserin, a 5-HT2A antagonist. Surprisingly, the decreasing immobility time in the FST in response to acute psilocin treatment was sustained for at least three weeks. In the novelty-suppressed feeding test (NSFT), the latency to feed, an indicator of anxiety-like behavior, was decreased by acute administration of psilocin; however, pretreatment with volinanserin did not diminish this effect. In contrast, DOI and TCB-2 did not affect the NSFT performance in mice. Furthermore, psilocin, DOI, and TCB-2 treatment did not affect the spontaneous locomotor activity or head-twitch response, a hallucination-like behavior in rodents. These results suggest that 5-HT2A contributes to the antidepressant effects of serotonergic psychedelics rather than an anxiolytic effects.

6.
Chemistry ; 28(60): e202202188, 2022 Oct 26.
Article in English | MEDLINE | ID: mdl-35934933

ABSTRACT

An effective method was developed for TfOH-catalyzed construction of spiroindanes and spirotetralines containing an all-carbon quaternary stereocenter. Intramolecular Friedel-Crafts-type 1,4-addition of the substrates which were di- or trimethoxybenzene and 2-cyclohexenone linked by an alkyl chain proceeded smoothly in the presence of 30 mol % of TfOH. A variety of spiroindanes and spirotetralines were obtained with moderate to excellent yield by this method. The reaction was successfully applied in the first total synthesis of the unusual proaporphine alkaloid (±)-misrametine, which included the gram-scale spirocyclization and selective O-demethylation used KCN in DMSO condition as key steps.


Subject(s)
Alkaloids , Antineoplastic Agents , Molecular Structure , Catalysis , Dimethyl Sulfoxide , Carbon
7.
Behav Brain Res ; 408: 113284, 2021 06 25.
Article in English | MEDLINE | ID: mdl-33819533

ABSTRACT

Habitual smoking in patients with schizophrenia (SCZ) is considered to improve their own psychoses or to develop a vulnerability to psychological dependence on (-)-nicotine ([-]-NIC) by stimulating nicotinic acetylcholine receptors (nAChRs) in the central nervous system. In the present study, we investigated whether habitual smoking is due to get therapeutic effect or to psychological dependence and which nAChR subunits are associated with them using mice that were repeatedly administered phencyclidine (PCP: 10 mg/kg/day, s.c. for 14 days) as SCZ-like model mice. Mice that were repeatedly administered PCP showed impairments in social or cognitive behaviors; decreased expression of α7 and/or α4 nAChR subunits in the prefrontal cortex (PFC); and increased expression of α7, α4, and ß2 nAChR subunits in the nucleus accumbens (NAc). These changes were attenuated by repeated administration of (-)-NIC. The attenuating effects on behavioral impairments were prevented by a selective α7 nAChR antagonist and a selective α4ß2 nAChR antagonist. At non- or weak effective dose by themselves, co-administration of (-)-NIC (0.03 mg/kg) and risperidone (0.03 mg/kg) showed synergistic effects on behavioral impairments in PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC in the PCP-administered mice. Repeated (-)-NIC administration did not affect the performance of conditioned place preference, while it showed behavioral sensitization to (-)-NIC and attenuating effect on haloperidol-induced catalepsy in the PCP-administered mice. Our findings suggest that habitual smoking in SCZ might be attributed to get therapeutic and reduce side effects mediated by α7 and α4ß2 nAChR activation by (-)-NIC.


Subject(s)
Behavior, Animal/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Nucleus Accumbens , Phencyclidine/pharmacology , Prefrontal Cortex , Receptors, Nicotinic , Social Behavior , Animals , Disease Models, Animal , Male , Mice , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Receptors, Nicotinic/drug effects , Receptors, Nicotinic/metabolism , Schizophrenia/metabolism , Smoking/metabolism , alpha7 Nicotinic Acetylcholine Receptor/drug effects , alpha7 Nicotinic Acetylcholine Receptor/metabolism
8.
Eur Neuropsychopharmacol ; 41: 92-105, 2020 12.
Article in English | MEDLINE | ID: mdl-33109433

ABSTRACT

The smoking incentive in patients with schizophrenia (SCZ) depends on stimulation of nicotinic acetylcholine receptors (nAChRs) in the central nervous system. To detect potential predictor genes for nicotine responses in SCZ, we explored common factor using research data in human and animal samples. In lymphoblastoid cell lines from SCZ, the mRNA expression level of α7 nAChR subunit was decreased. In SCZ-like model mice of phencyclidine (PCP; 10 mg/kg/day, subcutaneously for 14 days)-administered mice, the mRNA expression level of α7 nAChR subunit and protein expression level of α7 or α4 nAChR subunit were significantly decreased in the prefrontal cortex during PCP withdrawal. Protein, but not mRNA, expression levels of α7, α4, and ß2 nAChR subunits were significantly increased in the nucleus accumbens. Acute (-)-nicotine [(-)-NIC: 0.3 mg/kg, s.c.] treatment attenuated impairments of social behaviors and visual recognition memory. These effects of (-)-NIC were completely blocked by both methyllycaconitine, a selective α7 nAChR antagonist, and dihydro-ß-erythroidine (DHßE), a selective α4ß2 nAChR antagonist. (-)-NIC did not induce conditioned place preference, but enhanced sensitivity to methamphetamine-induced hyperactivity. These findings suggest that α7 nAChR is associated with development of disease and is implicated in the therapeutic effect of nicotine in SCZ. The smoking incentive in SCZ might be attributed to treat their own symptoms, rather than a result of (-)-NIC dependence, by stimulating α7 and/or α4ß2 nAChRs.


Subject(s)
Dependency, Psychological , Nicotine/therapeutic use , Phencyclidine/toxicity , Schizophrenia/chemically induced , Schizophrenia/metabolism , alpha7 Nicotinic Acetylcholine Receptor/biosynthesis , Adult , Animals , Cells, Cultured , Disease Models, Animal , Female , Humans , Male , Mice , Middle Aged , Nicotine/pharmacology , Nucleus Accumbens/chemistry , Nucleus Accumbens/drug effects , Nucleus Accumbens/metabolism , Schizophrenia/drug therapy , Social Interaction/drug effects , alpha7 Nicotinic Acetylcholine Receptor/agonists , alpha7 Nicotinic Acetylcholine Receptor/analysis
10.
Eur Neuropsychopharmacol ; 29(8): 914-924, 2019 08.
Article in English | MEDLINE | ID: mdl-31303267

ABSTRACT

Alterations of the glutamatergic system components, including N-methyl-d-aspartate (NMDA) receptors are relevant to the pathophysiology of schizophrenia. Repeated phencyclidine (PCP) administration induces several schizophrenia-like psychobehavioral abnormalities and decreases extracellular glutamate levels, which are associated with increased levels of glial glutamate and aspartate transporter (GLAST) in the prefrontal cortex (PFC) of mice. In the present study, we investigated the functional roles of GLAST in the emotional and cognitive abnormalities in mice following repeated PCP administration by using GLAST heterozygous (+/-) mice, since GLAST mutant mice are a useful tool for elucidating the contribution of glutamate dysfunction to the pathophysiology of schizophrenia. PCP-administered GLAST wild-type (+/+) mice showed enhancement of immobility in a forced swimming test, impairments of visual recognition memory in a novel object recognition test, decrease in high potassium (K+)-induced extracellular glutamate release, and overexpression of GLAST and S100 proteins in the PFC, compared to saline-administered GLAST+/+ mice. Such behavioral and neurochemical abnormalities were not observed in PCP-administered GLAST+/- mice. In conclusion, these results clearly suggest that genetic GLAST dysfunction and glial activation play important roles in the development of emotional and cognitive abnormalities in PCP-administered GLAST+/+ mice.


Subject(s)
Cognition Disorders/chemically induced , Emotions/drug effects , Excitatory Amino Acid Antagonists/adverse effects , Excitatory Amino Acid Transporter 1/metabolism , Neuroglia/drug effects , Phencyclidine/adverse effects , Animals , Cognition Disorders/metabolism , Disease Models, Animal , Emotions/physiology , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Amino Acid Transporter 1/genetics , Female , Male , Mice, Inbred C57BL , Mice, Transgenic , Neuroglia/metabolism , Phencyclidine/pharmacology , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Schizophrenia/metabolism
11.
Neurochem Int ; 128: 127-134, 2019 09.
Article in English | MEDLINE | ID: mdl-30998952

ABSTRACT

Blonanserin differs from other antipsychotic drugs, such as risperidone and olanzapine, and exhibits a higher affinity for dopamine-D2/3 receptors than for serotonin 5-HT2A receptors. We investigated the involvement of dopamine-D3 receptors in the effect of blonanserin on the social deficit observed in an animal model of schizophrenia and sought to elucidate the molecular mechanism underlying its action. Mice received phencyclidine (PCP: 10 mg/kg/day, s.c.), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, once a day for 14 consecutive days. We then evaluated the sociability, using a social interaction test, and the expression of GluN1 subunit, an essential subunit of the NMDA receptors, in these mice. Blonanserin significantly ameliorated the PCP-induced social deficit, whereas olanzapine and haloperidol did not. This effect of blonanserin was antagonized by 7-OH-DPAT, a dopamine-D3 receptor agonist, and SCH23390, a dopamine-D1 receptor antagonist. However, the ameliorating effect of blonanserin was not inhibited by DOI, a serotonin 5-HT2A receptor agonist. The PCP-induced social deficit was also ameliorated by U99194, a dopamine-D3 receptor antagonist and SKF38393, a dopamine-D1 receptor agonist, being effects antagonized by 7-OH-DPAT or SCH23390. Blonanserin significantly inhibited the decrease in the phosphorylation levels of GluN1 at Ser897 by protein kinase A (PKA) in the prefrontal cortex (PFC) in PCPadministered mice. These results suggest that activation of NMDA receptors due to Ser897-phosphorylation of GluN1 subunit, which is a step linked to dopamine-D1 receptor-PKA signaling through dopamine-D3 receptor antagonism in the PFC, is required for the ameliorating effect of blonanserin on the PCP-induced social deficit. These findings also provide in vivo evidence that blonanserin antagonism of the dopamine-D3 receptors may be useful as a novel treatment strategy and that the dopamine-D3 receptors can be a novel therapeutic target molecule for the social deficit observed in schizophrenia.


Subject(s)
Dopamine Antagonists/therapeutic use , Interpersonal Relations , Phencyclidine/toxicity , Piperazines/therapeutic use , Piperidines/therapeutic use , Receptors, Dopamine D3/antagonists & inhibitors , Schizophrenia/drug therapy , Animals , Disease Models, Animal , Dopamine Antagonists/pharmacology , Dose-Response Relationship, Drug , Hallucinogens/toxicity , Male , Mice , Mice, Inbred ICR , Piperazines/pharmacology , Piperidines/pharmacology , Schizophrenia/chemically induced
12.
Chem Pharm Bull (Tokyo) ; 66(10): 1006-1014, 2018.
Article in English | MEDLINE | ID: mdl-30270235

ABSTRACT

Centrally chiral bisoxazolines connected directly to a planar chiral [2.2]paracyclophane backbone were synthesized and evaluated as asymmetric ligands in Cu-catalyzed intermolecular ethanolic O-H insertion reactions of α-diazo esters. The reactivities and enantioselectivities of Cu complexes of the synthesized bisoxazoline ligands were lower than those of ligands without central chirality. However, planar chiral [2.2]paracyclophane-based bisoxazoline ligands with an inserted benzene spacer that had a sterically demanding isopropyl substituent showed good enantioselectivities in inter- and intramolecular aromatic O-H insertion reactions, without the aid of central chirality.


Subject(s)
Copper/chemistry , Drug Design , Hydroxides/chemistry , Polycyclic Compounds/chemistry , Polycyclic Compounds/chemical synthesis , Catalysis , Ligands , Molecular Structure , Stereoisomerism
13.
Org Lett ; 20(16): 5044-5047, 2018 08 17.
Article in English | MEDLINE | ID: mdl-30079736

ABSTRACT

The enantioselective total synthesis of an unusual pentacyclic proaporphine alkaloid, (-)-misramine, was achieved. The synthetic strategy relied on an enantioselective intramolecular Friedel-Crafts-type 1,4-addition using an asymmetric organocatalyst to construct a spiroindane skeleton containing an all-carbon quaternary stereocenter and a double reductive amination of the keto-aldehyde to form a piperidine ring toward the end of the synthesis. This work is the first example of asymmetric synthesis of a proaporphine alkaloid.

14.
Org Biomol Chem ; 16(10): 1770-1778, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29464253

ABSTRACT

Planar chiral [2.2]paracyclophane-based phosphine-phenol catalysts, which have a benzene ring spacer inserted between the pseudo-ortho-substituted [2.2]paracyclophanol skeleton and the diarylphosphino group, are highly suitable for enantioselective [3 + 2] annulations of allenoates and N-tosylimines. These catalysts can be tuned by changing the substituent on the benzene rings of the diarylphosphino group. The observed enantioselectivity of 92% is the highest reported to date for phosphine-catalyzed annulations of unsubstituted allenic esters and N-tosylaldimines.

15.
Org Biomol Chem ; 13(17): 4833-6, 2015 May 07.
Article in English | MEDLINE | ID: mdl-25805182

ABSTRACT

C2-symmetric planar chiral [2.2]paracyclophane-based bisoxazoline ligands, characterized by the inserted benzene spacer, which has a sterically demanding substituent, were synthesized and it was shown that up to 80% ee was obtained for the Cu-catalyzed O-H insertion reaction of α-diazo esters without the aid of the central chirality.


Subject(s)
Copper/chemistry , Oxazoles/chemical synthesis , Polycyclic Compounds/chemistry , Catalysis , Ligands , Molecular Structure , Oxazoles/chemistry
16.
Chem Commun (Camb) ; 49(38): 4030-2, 2013 May 11.
Article in English | MEDLINE | ID: mdl-23558930

ABSTRACT

A bis(thiourea) organocatalyst with a planar chiral [2.2]paracyclophane backbone has been synthesized and applied to the Henry reaction. The obtained high reactivity and enantioselectivity from the reaction of aromatic aldehydes with nitroalkanes suggested the significant potential of [2.2]paracyclophane to serve as the backbone of the organocatalyst.


Subject(s)
Ethers, Cyclic/chemistry , Piperidines/chemistry , Thiourea/analogs & derivatives , Aldehydes/chemistry , Alkanes/chemistry , Catalysis , Hydrocarbons, Aromatic/chemistry , Models, Molecular , Nitro Compounds/chemistry , Stereoisomerism
17.
Org Lett ; 14(6): 1366-9, 2012 Mar 16.
Article in English | MEDLINE | ID: mdl-22364480

ABSTRACT

The thermal reaction of 1,4-bisallenes with the aid of Cu salt/amine significantly suppressed the formal [3,3] sigmatropic rearrangement resulting in the highly selective formation of the bicyclo[4.2.0]octadiene framework. This reaction could be applied to the one-pot synthesis of bicyclo[4.2.0]octadienes from 1,5-hexadiynes via the Crabbé homologation.


Subject(s)
Alkadienes/chemical synthesis , Alkynes/chemistry , Bridged Bicyclo Compounds/chemical synthesis , Copper/chemistry , Alkadienes/chemistry , Amines/chemistry , Bridged Bicyclo Compounds/chemistry , Catalysis , Cyclization , Molecular Structure , Salts/chemistry
18.
Drug Metab Dispos ; 38(9): 1576-81, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20566696

ABSTRACT

The aim of the present study was to characterize the mechanism of erythromycin transport at the blood-placenta barrier, using TR-TBT 18d-1 cells as a model of rat syncytiotrophoblasts. [(14)C]Erythromycin was taken up by TR-TBT 18d-1 cells with a Michaelis constant of 466 microM. Although the uptake was not dependent on extracellular Na(+) or Cl(-), it was increased at weakly alkaline pH. Significant overshoot of [(14)C]erythromycin uptake by placental brush-border membrane vesicles was observed in the presence of an outwardly directed proton gradient. These results indicate that erythromycin is transferred by the H(+)-coupled transport system in syncytiotrophoblasts. To address the physiological transport of erythromycin in rat placenta, fetal-to-maternal transport clearance was estimated by means of the single placental perfusion technique. Clearance of [(14)C]erythromycin was higher than that of [(14)C]inulin, a paracellular pathway marker, and was decreased by the addition of 5 mM erythromycin, indicating that saturable efflux system from fetus to mother is involved. The effect of various transporter inhibitors on [(14)C]erythromycin efflux from TR-TBT 18d-1 cells was evaluated. cyclosporin A, fumitremorgin C, and probenecid had no effect, whereas ethylisopropylamiloride, a specific inhibitor of Na(+)/H(+) exchangers (NHEs), was significantly inhibitory. These results suggest that erythromycin efflux transport at the rat blood-placenta barrier is mediated by an erythromycin/H(+) antiport system, driven by H(+) supplied by NHEs.


Subject(s)
Erythromycin/pharmacokinetics , Maternal-Fetal Exchange , Animals , Female , Pregnancy , Protons , Rats
19.
Chemistry ; 16(17): 5173-83, 2010 May 03.
Article in English | MEDLINE | ID: mdl-20340116

ABSTRACT

Novel [{RhCl(CO)dppp}(2)]-catalyzed intramolecular carbonylative [2+2+1] cycloadditions of bis(phenylsulfonylallene) derivatives under CO, leading to the facile formation of bis(phenylsulfonyl)bicyclo[n.3.0] frameworks (n=4-6), have been developed. The terminal double bonds of both allenyl moieties served exclusively as the two pi-components. In particular, this newly developed method was shown to be a powerful tool for the construction of bicyclo[6.3.0]undecadienones, which have hardly been prepared by the known Pauson-Khand (-type) reactions. The bicyclo[7.3.0]dodecadienone homologue (one extra carbon) could be formed in rather low yields. Alternatively, novel cycloisomerizations of bis(phenylsulfonylallene) derivatives with catalysis by the same Rh(I) complex under N(2) readily produced the 3,4-dimethylene-2,5-bis(phenylsulfonyl)cyclononene and the corresponding cyclooctene and cycloheptene frameworks.


Subject(s)
Alkadienes/chemical synthesis , Combinatorial Chemistry Techniques , Rhodium/chemistry , Sulfones/chemical synthesis , Alkadienes/chemistry , Catalysis , Cyclization , Molecular Structure , Stereoisomerism , Sulfones/chemistry
20.
Angew Chem Int Ed Engl ; 48(11): 2007-11, 2009.
Article in English | MEDLINE | ID: mdl-19199306

ABSTRACT

No templates needed: The title reaction makes it easy to construct the bicyclo[6.3.0]undecadienone framework in high yields (see scheme). A template effect is not required to achieve this ring-closing reaction efficiently. The present method can be applied to the construction of bicyclo[5.3.0] and bicyclo[4.3.0] ring systems. Ts = p-toluenesulfonyl.


Subject(s)
Alkadienes/chemistry , Bridged Bicyclo Compounds/chemistry , Rhodium/chemistry , Catalysis , Cyclization
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