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At least 19 recordsLinked to original sources
PubMed1994

Adamantane as a brain-directed drug carrier for poorly absorbed drug. 2. AZT derivatives conjugated with the 1-adamantane moiety.

Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). In in vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degraded enzymatically and converted quantitatively to their parent drug. AZT. As assessed by octanol-buffer partitioning, the prodrugs were much more lipophilic than AZT and were expected to penetrate the blood-brain barrier (BBB) readily. In in vivo studies, in which the prodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7-18 times higher concentrations than AZT in spite of the negligible amount of the prodrug in the cerebrospinal fluid. These results indicate that the introduction to AZT of the 1-adamantane moiety results in the enhancement of the BBB penetration. This pharmaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.

Adamantane↗
PubMed1996

[Comparative study of the mechanism of inhibition of Sindbis virus reproduction by adamantane derivatives: remantadine and amide of 1-adamantane carboxylic acid].

Amide of 1-adamantane carboxylic acid (AACA), the same as remantadine, was shown to have no antiviral action and any influence on the efficiency of the Sindbis virus adsorption. However, it significantly inhibited the virus specific synthesis of RNA and protein. The main difference between AACA and remantadine was in the fact that the efficiency of the inhibition of the Sindbis virus reproduction and synthesis of the virus specific RNA in the presence of AACA did not markedly decrease even when AACA was added to the experimental system 7 hours after the adsorption whereas for the inhibitory effect of remantadine it was to be added to the system not later than 2 hours after the adsorption.

Adamantane↗
PubMed1991

Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study.

Recent studies from our laboratory have provided evidence that the 1-amino-adamantane derivative memantine (1-amino-3,5-dimethyl-adamantane) binds to the MK-801-binding site of the N-methyl-D-aspartate (NMDA)-receptor-gated ion channel. This action has been suggested to account for the antiparkinsonian and antispastic activity of the drug. In the present investigation we have extended our work by testing a series of 1-amino-adamantanes, including amantadine (1-amino-adamantane) and memantine, for their ability to compete with [3H]MK-801 binding in membrane homogenates of postmortem human frontal cortex. The most potent substance (1-amino-3,5-diethyl-adamantane) had a Ki-value of 0.19 +/- 0.06 microM while the weakest substance (1-N-methyl-amino-adamantane) had a Ki-value of 21.72 +/- 1.63 microM. The Ki-value of amantadine was 10.50 +/- 6.10 microM. In agreement with our earlier investigation, the Ki-value of memantine was 0.54 +/- 0.23 microM. The results indicate that 1-amino-adamantanes, in general, may produce their pharmacological effects through an interaction with the NMDA-receptor-gated ion channel. The displacement of [3H]MK-801 binding thus may provide the basis to predict the antiparkinsonian and antispastic activity of novel substituted 1-amino-adamantanes and possibly of other drugs.

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PubMed1997

Block of open channels of recombinant AMPA receptors and native AMPA/kainate receptors by adamantane derivatives.

1. The effects of two adamantane derivatives, 1-trimethylammonio-5-(1-adamantane-methyl-ammoniopentane dibromide) (IEM-1460) and 1-ammonio-5-(1-adamantane-methylammoniopentane dibromide) (IEM-1754) on kainate-induced currents were studied in Xenopus oocytes expressing recombinant ionotropic glutamate receptors and in freshly isolated neurones from rat hippocampal slices. 2. The adamantane derivatives caused use- and voltage-dependent block of open channels of recombinant AMPA receptors. This antagonism was dependent on receptor subunit composition; channels gated by recombinant, homomeric GluR1 and GluR3 receptors exhibited a higher sensitivity to block than those gated by receptors containing edited GluR2 subunits. In the former cases, IEM-1460 had an IC50 of 1.6 microM at a holding potential (Vh) of -80 mV and IEM-1754 was 3.8 times less potent than IEM-1460. In contrast, 100 microM IEM-1460 inhibited responses to 100 microM kainate of receptors containing edited GluR2 subunits by only 7.8 +/- 2.4% (n = 5 oocytes at a Vh of -80 mV. 3. Native AMPA/kainate receptors in isolated hippocampal cells were inhibited by adamantane derivatives in a use- and voltage-dependent manner. This antagonism was dependent on cell type: pyramidal neurones were less sensitive to IEM-1460 (IC50 = 1617 microM at Vh = -80 mV) than interneurones (IC50 = 1.6 microM at Vh = -80 mV). IEM-1460 and IEM-1754 were equipotent when applied to pyramidal neurones, but IEM-1754 was less potent (approximately 3 times) than IEM-1460 when applied to interneurones. 4. It is concluded that the presence of the edited GluR2 subunit in recombinant AMPA receptors and native AMPA/kainate receptors inhibits channel block by organic cations and that adamantane derivatives are potentially valuable tools for identifying classes of AMPA/kainate receptors and their roles in synaptic transmission.

Adamantane↗
PubMed1983

Cycloamylose complexation of adamantane derivatives.

Spectrophotometric and pH potentiometric studies indicate that cyclohexaamylose (alpha-cyclodextrin) and cycloheptaamylose (beta-cyclodextrin) form aqueous complexes with all adamantane derivatives examined to date. Thermodynamic complex formation constants are reported for the substrates 1-adamantaneamine (amantadine), 1-adamantaneammonium ion, 1-adamantanemethylamine, 1-adamantane-methylammonium ion, 1-adamantanecarboxylic acid, 1-adamantane-carboxylate ion, 1-adamantaneacetic acid and 1-adamantaneacetate ion. The existence of these complexes implies that cycloamylose might serve as a therapeutic sequestering agent for adamantane derivatives.

Adamantane↗
PubMed1997

Synthesis and antinociceptive activity of [D-Ala2]Leu-enkephalin derivatives conjugated with the adamantane moiety.

Based on the physicochemical and pharmacological properties of drugs having an adamantane skeleton, an adamantane-based moiety was evaluated as a drug carrier for poorly absorbed compounds, including peptides, active towards the central nervous system (CNS). Seven [D-Ala2]Leu-enkephalin derivatives conjugated with an adamantane-based moiety at the C-terminus or N-terminus were prepared by the solution-phase method and their biological activities were examined. The compounds derivatized at the C-terminus through an ester or amide linkage were much more lipophilic than the parent peptide and exhibited moderate in vitro opioid activity (guinea-pig ileum assay). Among them, four derivatives (1, 2, 4, 5), exhibited significant antinociceptive effects in an in vivo assay (mouse tail-pressure test) after subcutaneous administration. This result suggests that the introduction of the lipophilic adamantane moiety into [D-Ala2]Leu-enkephalin would improve the permeation of the poorly absorbed parent peptide through the blood-brain-barrier (BBB) without loss of antinociceptive effect.

Adamantane↗
PubMed2002

Electrophoretic behavior of adamantane derivatives possessing antiviral activity and their determination by capillary zone electrophoresis with indirect detection.

Separation and determination of adamantane derivatives with antiviral activity, namely amantadine (1-adamantan amine), memantine (1-amino-3,5-dimethyl adamantane) and rimantadine (alpha-methyl-1-adamantane methylamine), were examined by capillary zone electrophoresis. After optimization, an indirect detection method using 5 mM 4-methylbenzylamine in ethanol/water solution (1:4) as simultaneously absorbing and buffering background electrolyte with detection at 210 nm was found suitable for determination of the individual compounds (limit of detection was 0.35 mg L(-1) for memantine hydrochloride, S/N = 3). Baseline separation of all the three compounds was reached by addition of alpha- or beta-cyclodextrins to the electrolyte in concentrations of 20 and 2 mM, respectively.

Amantadine↗
PubMed1983

Identification of hydrophobic regions of the calcium-transport ATPase from sarcoplasmic reticulum after photochemical labeling with adamantane diazirine.

The Ca-ATPase from skeletal muscle sarcoplasmic reticulum was labeled with [3H]adamantane diazirine. Adamantane diazirine is a hydrophobic photoactivated probe that partitions into the cell membrane and can be used to identify regions of proteins that are embedded within the membrane. Digestion of the labeled protein with trypsin and separation of the labeled tryptic fragments by SDS-polyacrylamide-gel electrophoresis indicated that all of the major tryptic fragments were labeled by the probe. The presence of glutathione in the sample buffer during photolysis did not alter the pattern of labeling, indicating that adamantane diazirine labeled the Ca-ATPase from within the lipid bilayer. These results indicate that the Ca-ATPase polypeptide must cross the membrane at least 3 times.

Adamantane↗
PubMed1998

How to overcome resistance of influenza A viruses against adamantane derivatives.

We tested two approaches to overcoming resistance of influenza A viruses against adamantane derivatives. First, adamantane derivatives that interfere with the ion channel function of the variant M2 protein of amantadine-resistant viruses may prevent drug resistance, if they are used in mixture with amantadine. Second, amantadine acts on the M2 protein (at low concentrations) and indirectly on the hemagglutinin (at concentrations at least 100 times higher). Identifying and using a drug that reacted with both targets at the same concentration might reduce development of resistance, since, in this case, two mutations, one in each target protein would be necessary at once. Such a double mutation is assumed to be a rare event. We evaluated forty adamantane derivatives and two related compounds to determine whether they interfered with plaque formation by influenza A strains, including A/Singapore/1/57 (H2N2). Variants resistant to drugs that interfered at low concentrations (approximately 1 microg/ml; e.g. amantadine) were cross-resistant with each other, but were sensitive to those agents effective at high concentrations (8 microg/ml; e.g. memantine). The former group of compounds act on the ion channel; the corresponding escape mutants tested had amino acid replacements at positions 27, 30 or 31 of the M2 protein. Hemagglutinin was the indirect target of the latter group of compounds. Variants resistant to these agents lacked amino acid replacements within the ion channel of the M2 protein and the mutants tested had amino acid replacements in the hemagglutinin. Although we failed to identify compounds that interacted with the ion channel of amantadine-resistant variants and inhibited their replication, we were able to construct at least two compounds that interfered with both the ion channel and the hemagglutinin at about the same concentration. After passage in the presence of these compounds, we either failed to obtain any drug-resistant mutants or those obtained had amino acid replacements in the ion channel of the M2 protein and the hemagglutinin.

Adamantane↗
PubMedDate not supplied

Synthesis, hybridization properties, nuclease stability, and cellular uptake of the oligonucleotide--amino-beta-cyclodextrins and adamantane conjugates.

Synthesis of the oligonucleotides conjugated with amino derivatives of beta-cyclodextrin and adamantane, at the 3'-end of host oligonucleotide, has been described. The oligonucleotide conjugates were examined for their nuclease stability, hybridization properties, and cellular uptake. The oligonucleotide conjugates had increased nuclease resistance compared to their parent oligonucleotides. Conjugation of adamantane to the oligonucleotides did not adversely affect the ability of the oligonucleotides to hybridize with their complementary RNA. Conjugation with amino derivatives of beta-cyclodextrin, however, significantly destabilized the duplex formation. In the cellular uptake studies, we found that amino derivatives of beta-cyclodextrin attached at 3'-end of the oligonucleotides did not help to increase the uptake by cells. Cellular uptake of oligonucleotide-adamantane conjugates in association with 2-(hydroxypropyl)-beta-cyclodextrin (HPCD) as a "carrier" was significantly higher than that of control oligonucleotides.

Adamantane↗
PubMed1992

[Effect of various adamantane compounds on the reproduction of Sindbis virus. Isolation and properties of a resistant strain].

Rimantadine and its structural analogs, i. e. amide of 1-adamantane carboxylic acid (AACA) and 1-adamantane acetic acid amide, were shown to be able to inhibit reproduction of Sindbis virus in culture Vero cells. AACA had the maximum antiviral activity. Subcultures of the initial sensitive population of Sindbis virus in the presence of AACA led to formation of mutants resistant to AACA as well as to rimantadine, adamantane acetic acid amide and ammonium chloride. The Sindbis virus population was heterogenous in sensitivity to AACA, which was evident from isolation of separate clones with various levels of sensitivity to the above mentioned compounds from the population. It was found that reproduction of the AACA sensitive and resistant strains of Sindbis virus differed: the latent period of the resistant strain was 2 hours longer than that of the sensitive strain. The same effect was observed in the comparative study on synthesis of the virus-specific RNA.

Animals↗
PubMed1998

High-speed magic-angle spinning 13C MAS NMR spectra of adamantane: self-decoupling of the heteronuclear scalar interaction and proton spin diffusion.

We have investigated the carbon line shape of solid adamantane under high-speed magic-angle sample spinning (MAS) acquired without proton decoupling. The CH-group shows a spinning-speed-dependent line broadening while the CH2-group consists of a spinning-speed-independent sharp component and a spinning-speed-dependent broader part. These phenomena can be explained by self-decoupling of the J-interaction due to proton spin diffusion. Such a self-decoupling process can be described by a magnetization exchange process between the multiplet lines. Changing the spin-diffusion rate constant by off-resonance irradiation of the protons allows us to observe the full range from slow exchange to coalescence to fast exchange of the carbon spectra. One of the multiplet components in the CH2-group corresponds to a group spin of the protons of zero and therefore does not couple to the other protons. This gives rise to the sharp central line. The magnetization exchange rate constant between the different multiplet lines can be determined from the spectra and is a measure for the spinning-speed-dependent proton spin-diffusion rate constant. Even at an MAS speed of 30 kHz, proton spin diffusion is still observable despite the relatively weak intermolecular proton dipolar-coupling network in adamantane which results in a static proton line width of only 14 kHz (full width at half height).

Adamantane↗
PubMed1999

Inhibition of HIV-1 replication by newly developed adamantane-containing polyanionic agents.

Newly developed antiviral compounds consisting of an adamantane derivative chemically linked to a water-soluble polyanionic matrix were shown to inhibit HIV-1 infection in lymphoblastoid cells, HeLa CD4+ beta-galactosidase (MAGI) cells and macrophages. The effect of the compounds was recorded by measuring viral reverse transcriptase activity and p24 by ELISA in culture supernatant and by immunoblotting of cell lysates. In this paper we describe the data obtained with one of the most promising compounds, Amant. Amant was not toxic for the host cells at concentrations as high as 1 mg/ml. The inhibition of HIV-1 replication in MT-4 and MAGI cells was observed when Amant was added either before infection or with the virus (0 h of infection), and was expressed even when the compound added at 0 h was removed 1.5 h after infection. Its inhibitory concentration (IC50) against HIV-1 and HIV-2 replication was 2-6 and 93 microg/ml, respectively. The anti-HIV-1 effect of the compound was gradually decreased when it was added 1 and 2 h post infection, and no inhibition was observed when the compound was added 4 h after infection, suggesting that the compound as a membranotropic drug blocks an early step of replication. It completely prevented the transport of Gag proteins into the nuclei. Pretreatment of the virus with Amant did not reduce its infectious activity. The classical adamantane derivatives amantadine and rimantadine hydrochloride did not inhibit HIV replication.

Adamantane↗
PubMed1991

Crystal structures of cytochrome P-450CAM complexed with camphane, thiocamphor, and adamantane: factors controlling P-450 substrate hydroxylation.

X-ray crystal structures have been determined for complexes of cytochrome P-450CAM with the substrates camphane, adamantane, and thiocamphor. Unlike the natural substrate camphor, which hydrogen bonds to Tyr96 and is metabolized to a single product, camphane, adamantane and thiocamphor do not hydrogen bond to the enzyme and all are hydroxylated at multiple positions. Evidently the lack of a substrate-enzyme hydrogen bond allows substrates greater mobility in the active site, explaining this lower regiospecificity of metabolism as well as the inability of these substrates to displace the distal ligand to the heme iron. Tyr96 is a ligand, via its carbonyl oxygen atom, to a cation that is thought to stabilize the camphor-P-450CAM complex [Poulos, T. L., Finzel, B. C., & Howard, A. J. (1987) J. Mol. Biol. 195, 687-700]. The occupancy and temperature factor of the cationic site are lower and higher, respectively, in the presence of the non-hydrogen-bonding substrates investigated here than in the presence of camphor, underscoring the relationship between cation and substrate binding. Thiocamphor gave the most unexpected orientation in the active site of any of the substrates we have investigated to date. The orientation of thiocamphor is quite different from that of camphor. That is, carbons 5 and 6, at which thiocamphor is primarily hydroxylated [Atkins, W. M., & Sligar, S. G. (1988) J. Biol. Chem. 263, 18842-18849], are positioned near Tyr96 rather than near the heme iron. Therefore, the crystallographically observed thiocamphor-P-450CAM structure may correspond to a nonproductive complex. Disordered solvent has been identified in the active site in the presence of uncoupling substrates that channel reducing equivalents away from substrate hydroxylation toward hydrogen peroxide and/or "excess" water production. A buried solvent molecule has also been identified, which may promote uncoupling by moving from an internal location to the active site in the presence of highly mobile substrates.

Adamantane↗
PubMed1987

Adamantane derivatives: a new class of insulin secretagogues.

Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property. At a non-stimulatory concentration of glucose (3 mM), 1-adamantanamine (1 mM) reversibly inhibited 86Rb efflux from islet cells, depolarized the beta-cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2+ abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux. At a stimulatory concentration of glucose (10 mM), 1-adamantanamine reversibly increased 86Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose-dependent, with a threshold concentration of 10 microM for stimulation release. 2-Adamantanamine was as potent as 1-adamantanamine. In contrast, substitution of the amino group by a carboxyl group (1-adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1-adamantanol) suppressed it. It is concluded that adamantane derivatives bearing an amino group decrease K+ permeability of the beta-cell membrane and thereby cause depolarization. This activates voltage-dependent Ca channels, permits Ca2+ influx and eventually stimulates insulin release. They may also mobilize cellular Ca2+, but this effect is not sufficient to cause release.

Adamantane↗
PubMed1999

[Adamantane derivatives enhancing body's resistance to emergencies].

A total of 329 novel adamantane derivatives have been synthesized and pharmacologically studied. Among them, the compounds containing halogen-containing aromatic radicals in the second position show the most pronounced effect on animal resistance to the emergencies induced by its habitat and performance. N-(2-adamantyl)-N-(para-bromphenyl)amine (bromantane) possesses a low toxicity, a high ability to enhance the physical and operant working maintenance of animals, to accelerate its recovery in developed fatigue, in hyperthermia and hypoxia in particular. 2-(para-chlorobenzoylamine)adamantane (chlodantane) has the processes of a rapid-action adaptogenic agent by enhancing the resistance of animals to various physical and toxically chemical noxious agents. The two compounds have immunostimulating effects in secondary stress-induced immunodeficiencies whose mechanism of action is a membranous protective activity.

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