Biomedical subjects

H Rapoport

Publications and source records attributed to H Rapoport.

At least 19 recordsLinked to original sources

PubMed2005

[Dental treatment for patients with myasthenis gravis].

Myasthenia gravis is an autoimmune disease, characterized by weakness of the skeletal muscles, which increases during action. The nature of the disease influences the mode of dental treatment. Careful treatment planning prevents over-activity of the muscles. The bulbar appearance of the disease, affects the chewing muscles, thus, it is important to avoid aspiration of foods or other particles from the mouth. Infections may exacerbate the symptoms of Myasthenia gravis, therefore the dentist must eliminate oral focal infections and avoid using medicines that might worsen the disease.

Aged↗

PubMed2001

Enantiospecific synthesis of annulated nicotine analogues from D-glutamic acid. 7-Azabicyclo[2.2.1]heptano[2.3-c]pyridines.

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2.2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifically from D-glutamic acid. The method involved a lithium cis-2,6-dimethylpiperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-butyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem with a standard decarboxylation sequence. Reductive amination afforded the desired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the corresponding iodopyridinylproline methyl ester, obtained via ultrasound-facilitated chloro-iodo exchange, was also effected.

Aza Compounds↗

PubMed2000

Preparation of functionalized, conformationally constrained DTPA analogues from L- or D-serine and trans-4-hydroxy-L-proline. Hydroxymethyl substituents on the central acetic acid and on the backbone.

The enantio- and diastereospecific syntheses of conformationally constrained diethylenetriaminepentaacetic acid (DTPA) analogues that are functionalized with a hydroxymethyl linker substituent on the central acetic acid or on the backbone are described. Key synthetic steps include (i) displacement of the 4-hydroxyl group of N-BOC-trans-4-hydroxy-L-proline benzyl ester, via activation as the triflate, with suitable amines derived from L- or D-serine, (ii) the low-temperature alkylation of diethylenetriamines with the triflate of benzyl glycolate, thereby minimizing competitive lactamization, to give DTPA pentabenzyl esters, and (iii) deprotection to afford the corresponding DTPA analogues under very mild hydrogenolysis conditions.

Acetic Acid↗

PubMed1998

Are migrant minorities strategically self-selected?

"In this paper we focus on the possibility of migrants' self-selection through strategic remittances. We argue that migrants of a specific community might be pooled with migrants from other ethnic minorities on the labor market of the foreign host country and that this could reduce the occurrence of strategic remittances. In a simple model with two types of workers, skilled and unskilled, facing two possible actions, to migrate or not to migrate, we derive the theoretical conditions under which strategic transfers are still operating when pooling among communities is introduced."

Culture↗

PubMed1996

Methylation inhibitors can increase the rate of cytosine deamination by (cytosine-5)-DNA methyltransferase.

The target cytosines of (cytosine-5)-DNA methyltransferases in prokaryotic and eukaryotic DNA show increased rates of C-->T transition mutations compared to non-target cytosines. These mutations are induced either by the spontaneous deamination of 5-mC-->T generating inefficiently repaired G:T rather than G:U mismatches, or by the enzyme-induced C-->U deamination which occurs under conditions of reduced levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy). We tested whether various inhibitors of (cytosine-5)-DNA methyltransferases analogous to AdoMet and AdoHcy would affect the rate of enzyme-induced deamination of the target cytosine by M.HpaII and M.SssI. Interestingly, we found two compounds, sinefungin and 5'-amino-5'-deoxyadenosine, that increased the rate of deamination 10(3)-fold in the presence and 10(4)-fold in the absence of AdoMet and AdoHcy. We have therefore identified the first mutagenic compounds specific for the target sites of (cytosine-5)-DNA methyltransferases. A number of analogs of AdoMet and AdoHcy have been considered as possible antiviral, anticancer, antifungal and antiparasitic agents. Our findings show that chemotherapeutic agents with affinities to the cofactor binding pocket of (cytosine-5)-DNA methyltransferase should be tested for their potential mutagenic effects.

Bacteria↗

PubMed1993

Novel anti-inflammatory undecapeptides that contain anisolyated glutamic acid derivatives.

In various animal models of tissue injury, corticotropin-releasing factor (CRF) and related peptides inhibit swelling, edema and loss of protein from the vascular compartment. To search for smaller peptide segments of CRF that might retain anti-inflammatory activity, the authors tested peptides similar to the carboxy terminals of ovine (o) and human/rat (h/r) CRF. Also, because h/rCRF(35-39), -Arg-Lys-Leu-Met-Glu-, resembles Arg-Lys-Leu-Leu-Glu-, a sequence found in many intermediate filament proteins, analogous peptides were evaluated. Ovine CRF(21-41), -Met-Thr-Lys-Ala-Asp-Gln-Leu-Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys- Leu-Asp-Ile-Ala-NH2, its carboxy terminal carboxyl derivative, oCRF(21-41)-OH, and the fragments, oCRF(26-41) and oCRF(30-41), were inactive when assayed at 5 mg/kg i.v. on edema induced in the pentobarbital-anesthetized rat's hindpaw after immersion in 58 degrees C water for 1 min. Crude peptides, D-Leu-Ala-Thr-D-Tyr-Arg-Lys-Leu-Leu-Glu-Ile-D-Leu-NH2 and D-Ala-His-Ser-D-Asn-Arg-Lys-Leu-Leu-Glu-Ile-D-Leu-NH2, were found to have activity in this bioassay. Characterization of the structures within the crude mixture revealed that substitution of the glutamic acid residue with an anisolyated glutamic acid (2-amino-5-(methoxyphenyl)-5-oxopentanoic acid) derivative, designated as (A*), increased the overall potency. The glutamyl-anisole derivative was a by-product of the temperature-dependent Friedel-Crafts acylation reaction that occurs during hydrogen fluoride cleavage of glutamyl-containing peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1991

Nicotinic pharmacology of anatoxin analogs. I. Side chain structure-activity relationships at peripheral agonist and noncompetitive antagonist sites.

Anatoxin analogs were designed to evaluate the importance of H-bonding, planarity, size and steric configuration of the anatoxin side chain moiety with regard to nicotinic potency and efficacy. This report examines the actions of these analogs on the somatic nicotinic acetylcholine receptor at two different loci: the agonist recognition site and the ion channel site. Agonist effects were evaluated using stimulation of contracture and radioligand binding competition for [125I]alpha bungarotoxin sites in Rana pipiens muscle, and stimulation of [3H]perhydrohistrionicotoxin binding and competition for [125I]alpha bungarotoxin sites in Torpedo californica electric organ. Antagonist effects were evident in the inhibition of neurally evoked twitch of the frog sciatic nerve-sartorius muscle preparation and in inhibition of [3H]perhydrohistrionicotoxin binding to Torpedo receptors. The affinity of these analogs for the agonist locus was consistently associated with activation of the AChR. Our results show that side chain steric configuration has an important role in affinity of the (+)-anatoxin-a analogs for the nicotinic acetylcholine receptor ion channel sites. Several analogs also revealed stereospecific noncompetitive actions. The (+)-anatoxin-a-related structures are important probes for characterizing both agonist and ion channel target sites on the peripheral nicotinic receptor.

Amphibian Venoms↗

PubMed1991

Nicotinic pharmacology of anatoxin analogs. II. Side chain structure-activity relationships at neuronal nicotinic ligand binding sites.

Eighteen analogs of (+)-anatoxin-a were evaluated for nicotinic potency at two putative nicotinic acetylcholine receptor sites in the central nervous system. The affinities of the analogs for [3H]nicotine and [125I]alpha-bungarotoxin binding sites were compared. This series of analogs, with modifications to the side chain moieties of the parent structure, enables the importance (for nicotinic binding) of hydrogen bonding strength, planarity, size and steric configuration of this region of the molecule to be assessed. These studies confirm the importance of the side chain stereochemistry and the subordinate role of H-bonding strength of anatoxin analogs. Of all the analogs tested, the parent compound (+)-anatoxin-a is the most potent competitor of ligand binding. Although all analogs have higher affinity at the [3H](-)-nicotine site compared to the alpha-[125I]bungarotoxin site, the rank order of potency is generally the same at both central nervous system sites, and agrees with the order at the muscle nicotinic receptor. However, the simple methoxyamide and the isoxazolidide analogs appear more selective for the neuronal nicotinic receptor subtype identified by [3H](-)-nicotine, indicative of structural differences among the agonist recognition sites.

Animals↗

PubMed1990

Activation and blockade of the acetylcholine receptor-ion channel by the agonists (+)-anatoxin-a, the N-methyl derivative and the enantiomer.

The effects of (+)- and (-)-anatoxin-a (AnTX) and N-methylanatoxin (M-AnTX) on peripheral nicotinic ion channel activity were studied using high micromolar concentrations. Whereas (+)-AnTX is an effective agonist at nanomolar concentrations, (-)-AnTX and M-AnTX were effective at low micromolar concentrations. The binding of [3H]perhydrohistrionicotoxin to the nicotinic acetylcholine receptor-ion channel was stimulated by the above agonist concentrations, but [3H]perhydrohistrionicotoxin binding was inhibited at high micromolar concentrations of each of the toxins. In single channel recordings, these toxins exhibited ion channel blocking properties; the concentration- and voltage-dependent kinetics of each were essentially the same. In the case of (+)-AnTX, desensitization was also present at micromolar concentrations. These data show that ion channel blockade may be a property of many anatoxin-a analogs, and that in the particular case of analogs with low agonist potency, ion channel blockade may be a concomitant primary effect of the toxins. Stereospecificity and number of amine moieties did not influence the ion channel blocking characteristics in this series of molecules, although these factors strongly modified agonist potency.

Amphibian Venoms↗

PubMed1989

Cyclic carbamate analogues of pilocarpine.

A number of pilocarpine analogues containing the (S)-3-ethyl-4-[(4'-imidazolyl)methyl]-2-oxazolidinone (9) structural feature were synthesized from L-histidine. With 1-benzyl-L-histidine as the key intermediate, a regiospecific synthetic route was developed to the N pi-methyl derivative 8. The regiochemistry of the alkylation of the imidazole nucleus was determined by measuring proton cross-ring coupling constants in the high-field 1H NMR. The effects on muscarinic receptors of these variously alkylated derivatives 6-10 were studied on isolated guinea pig ileum. The derivatives in which the imidazole nitrogen was unsubstituted (9), N tau-methylated (10), and N pi-methylated (8) were cholinergic muscarinic agonists with an increasing order of potency; compounds 6 and 7 were inactive. Analogue 8 with the same substitution pattern as pilocarpine was equipotent with pilocarpine, making these hydrolytically stable carbamate derivatives potentially useful drugs.

Animals↗

PubMed1989

N-methylanatoxinol isomers: derivatives of the agonist (+)-anatoxin-a block the nicotinic acetylcholine receptor ion channel.

Using biochemical and patch-clamp techniques, we investigated the pharmacology of S- and R-epimers of N-methylanatoxinol, which are analogs of the semi-rigid, stereoselective, nicotinic agonist (+)-anatoxin-a. In contrast to (+)-anatoxin-a, both isomers had poor ability to inhibit the binding of 125I-alpha-bungarotoxin or to open acetylcholine channels, and they were unable to elicit contracture of frog rectus abdominis muscles. However, both isomers were able to demonstrate significant concentration-dependent blockade of the nicotinic acetylcholine receptor ion channel. The R-isomer was approximately 4-fold more potent in causing inhibition of [3H]H12HTX binding than was the S-isomer, in the absence of carbamylcholine. In the presence of carbamylcholine, the affinity of the R-isomer of N-methylanatoxinol for the ion channel sites was further enhanced, so that its affinity became much greater than that of the S-isomer. Refinement of voltage- and concentration-dependent terms for the ion channel blocking and unblocking rates yielded functions that were able to predict the channel open times and short closed times well. The S-isomer bound and dissociated from the ion channel site of the nicotinic acetylcholine receptor more rapidly and with greater voltage sensitivity than the R-isomer. The present characterization of the antagonistic properties of these new analogs of (+)-anatoxin-a introduces a new aspect to the molecular pharmacology of (+)-anatoxin-a analogs; the semi-rigid compounds could be useful in describing the allosteric binding sites of the acetylcholine receptor, as well as in delimiting the agonist binding site.

Animals↗

PubMed1988

Exclusive A-ring linkage for singly attached phycocyanobilins and phycoerythrobilins in phycobiliproteins. Absence of singly D-ring-linked bilins.

Previous spectroscopic studies on the phycocyanobilin-containing peptide beta-2T from Synechococcus sp. 6301 C-phycocyanin and the phycoerythrobilin-containing peptide beta-2TP from Porphyridium cruentum B-phycoerythrin indicated a different single thioether mode of attachment, postulated to be through the D-ring of the tetrapyrrole, in contrast to the A-ring linkage established for the other singly linked bilins in these proteins (Bishop, J.E., Lagarias, J.C., Nagy, J. O., Schoenleber, R.W., Rapoport, H., Klotz, A.V., and Glazer, A.N. (1986) J. Biol. Chem. 261, 6790-6796; Klotz, A.V., Glazer, A.N., Bishop, J.E., Nagy, J.O., and Rapoport, H. (1986) J. Biol. Chem. 261, 6797-6805). The crystal structure of Agmenellum quadruplicatum C-phycocyanin at 2.5-A resolution (Schirmer, T., Bode, W., and Huber, R. (1987) J. Mol. Biol., 196, 677-695) supports an A-ring linkage for all three phycocyanobilins. Consequently we have re-evaluated our proposed structural assignments by further 1H NMR studies. Two-dimensional homonuclear correlated and nuclear Overhauser enhancement spectroscopic data presented here show that all three bilins in Synechococcus 6301 C-phycocyanin are attached solely through the A-ring, complementary to the crystallographic data. The evidence from the NMR data for all bilin peptides examined includes the dipoledipole interactions of the 5-H with the 3-H, 3'-H, and a pyrrole methyl group (7-CH3); the corresponding interactions would not be possible in a D-ring-linked bilin. The 5-H also consistently exhibits allylic J-coupling to the 3-H, supporting A-ring linkage assignment. These data are inconsistent with the alternative D-ring linkage assignment since this would involve J-coupling through five bonds. Examination of the phycoerythrobilin beta-2 position in B-phycoerythrin also reveals an A-ring type of attachment by similar criteria. We conclude that all singly linked bilins are attached through the A-ring.

Chemical Phenomena↗

PubMed1988

Methyllycaconitine and (+)-anatoxin-a differentiate between nicotinic receptors in vertebrate and invertebrate nervous systems.

Specific high-affinity binding sites for 125I-alpha-bungarotoxin and (-)-[3H]nicotine have been measured in rat brain and locust (Schistocerca gregaria) ganglia. The binding sites for 125I-alpha-bungarotoxin had similar Kd values of 1.5 x 10(-9) and 0.8 x 10(-9) M for rat and locust preparations, respectively; the corresponding values for the (-)-[3H]nicotine-binding site were 9.3 x 10(-9) and 1.7 x 10(-7) M. Methyllycaconitine (MLA) potently inhibited 125I-alpha-bungarotoxin binding in both rat and locust. MLA was a less effective inhibitor of (-)-[3H]nicotine binding whereas (+)-anatoxin-a was a very potent inhibitor at this site in the rat but not in the locust. These data suggest that (+)-anatoxin-a is a useful probe for the high-affinity nicotine-binding receptor in vertebrate brain, whereas MLA is a preferential probe for the subclass of receptor that binds alpha-bungarotoxin.

Aconitine↗

PubMed1987

Nicotinic acetylcholine receptors in cultured neurons from the hippocampus and brain stem of the rat characterized by single channel recording.

Single channel recording techniques have been applied to neurons cultured from the hippocampus and the respiratory area of the brain stem of fetal rats in order to search for nicotinic acetylcholine receptors (nAChR) in the central nervous system. In addition to acetylcholine (ACh), the potent and specific agonist (+)-anatoxin-a was also used to characterize nicotinic channels. nAChRs were concentrated on the somal surface near the base of the apical dendrite, and in some patches their density was sufficient to record 2 or more channel openings simultaneously. Although a multiplicity of conductance states was also evident, the predominant population showed a single channel conductance of 20 pS at 10 degrees C. Thus, these neuronal nAChRs resembled the embryonic or denervated-type nAChRs in muscle. However, channel opening and closing kinetics were faster than reported for similar conductance channels in muscle. Therefore the nicotinic channels described here are similar but not identical to those of the well-characterized muscle nAChR, in agreement with biochemical, pharmacological, and molecular genetic studies on brain AChR.

Animals↗

PubMed1987

Nitrogen-bridged conformationally constrained etorphine analogues. Synthesis and biological evaluation.

Three N-C8-bridged analogues 4-6 of the opiate etorphine (3) were synthesized and evaluated for opiate agonism and antagonism. In each case ring closure was effected by intramolecular N-alkylation with a suitably developed C8 side chain. Another key synthetic step was the selective monoprotection of diol 11, which allowed independent elaborations of the C7 and C8 side chains. All three analogues showed distinctly diminished agonist activities when compared to the corresponding N-methyl compound, 19(R)-n-butylorvinol (3). Furthermore, no antagonist activity was detectable. The results demonstrate that the conformation at the amino nitrogen in rigid morphinans is critical for potent opiate activity.

Analgesia↗

PubMed1986

Phycobiliprotein-bilin linkage diversity. I. Structural studies on A- and D-ring-linked phycocyanobilins.

Phycocyanobilin (PCB) peptides alpha-1 PCB and beta-2T PCB were obtained by proteolytic degradation of Synechococcus 6301 C-phycocyanin. These peptides were found to have the following sequences. alpha-1 PCB Cys(PCB)-Ala-Arg beta-2T PCB Ile-Thr-Gln-Gly-Asp-Cys(PCB)-Ser-Ala. The peptides were examined by 1H NMR, circular dichroism spectroscopy, and secondary ion mass spectrometry. The 1H NMR data confirmed that in each case the bilin was attached through a single linkage, a thioether bond between the cysteinyl residue and the tetrapyrrole moiety. Comparison of the 1H NMR spectra of these peptides with those of appropriate model compounds showed that the thioether linkage in alpha-1 PCB was to the C-3' position and that in beta-2T PCB to the C-18' position on the bilin. Refluxing in neutral methanol under nitrogen led to the release of PCB from alpha-1 PCB but did not release the D-ring-linked tetrapyrrole from beta-2T. The above results together with those of an earlier study (Lagarias, J. C., Glazer, A. N., and Rapoport, H. (1979) J. Am. Chem. Soc. 101, 5030-5037) complete the determination of the mode of linkage of each of the three bilins on C-phycocyanin; two are linked through ring A and one through ring D. This is the first documented report of a singly D-ring-linked bilin.

Circular Dichroism↗

PubMed1986

Phycobiliprotein-bilin linkage diversity. II. Structural studies on A- and D-ring-linked phycoerythrobilins.

The discovery that the phycocyanobilin group attached to Cys-155 of the beta subunit of C-phycocyanin is D-ring linked (Bishop, J. E., Lagarias, J. C., Nagy, J. O., Schoenleber, R. W., Rapoport, H., Klotz, A. V., and Glazer, A. N. (1986) J. Biol. Chem. 261, 6790-6796) prompted examination of the linkage mode for phycoerythrobilin (PEB) groups attached at the corresponding position in other biliproteins. Appropriate small peptides were obtained by exhaustive enzymatic digestion of Porphyridium cruentum R-phycocyanin (peptide R-PC beta-2TP PEB) and B-phycoerythrin (peptide B-PE beta-2TP PEB). These peptides had the following structures R-PC beta-2TP PEB Gly-Asp-Cys(PEB)-Ser-Ser B-PE beta-2TP PEB Cys(PEB)-Thr-Ser. The spectroscopic and chemical properties of these peptides were compared with those of P. cruentum B-phycoerythrin peptide alpha-1 PEB, Cys(PEB)-Tyr-Arg, in which the bilin is A-ring linked (Schoenleber, R. W., Leung, S.-L., Lundell, D. J., Glazer, A. N., and Rapoport, H. (1983) J. Am. Chem. Soc. 105, 4072-4076). The PEB groups in peptides R-PC beta-2TP PEB and B-PE beta-2TP PEB were shown to be D-ring linked on the basis of the following criteria. Secondary ion mass spectrometry showed the bilins in these peptides and in alpha-1 PEB to have the same mass. The 18'-CH3, 18'-H, and 15-H resonances in the 1H NMR spectra of R-PC beta-2TP PEB and B-PE beta-2TP PEB appear significantly upfield from the corresponding thioether-linked ring A resonances seen in the spectrum of peptide alpha-1 PEB. The CD spectra of the two former peptides showed a strong positive Cotton effect at 300 nm. Such a Cotton effect is absent from the CD spectrum of peptide alpha-1 PEB and those of other A-ring-linked PEB peptides. Refluxing in methanol led to a near-quantitative release of PEB from alpha-1 PEB but no release from R-PC beta-2TP PEB and less than 20% release from B-PE beta-2TP PEB. In conjunction with earlier studies, these results show that distinctive amino acid sequences are found about the attachment sites for A-ring-linked, D-ring-linked, and dilinked (A- and D-ring-linked) bilins on the alpha and beta subunits of cyanobacterial and red algal phycobiliproteins and that the mode of linkage can be correctly predicted from inspection of the amino acid sequence.

Amino Acid Sequence↗

PubMed1986

Synthesis and radiolabeling of heterocyclic food mutagens.

The imidazoquinoline and imidazoquinoxaline food mutagens found in cooked meat are being synthesized by unambiguous methods that allow for the preparation of sufficient quantities of material for biological studies. These methods avoid difficult separations of regioisomeric mixtures of products and are designed to allow incorporation of specific high level tritium labeling.

Animals↗