Alpha Methylbenzylamine

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F.f. Knapp - One of the best experts on this subject based on the ideXlab platform.

  • Effects of configuration on the myocardial uptake of radioiodinated 3(R)-BMIPP and 3(S)-BMIPP in rats.
    Journal of nuclear medicine : official publication Society of Nuclear Medicine, 1997
    Co-Authors: Qun Lin, K.r. Ambrose, A.l. Beets, H. Luo, D.w. Mcpherson, F. Mokler, Joachim Kropp, F.f. Knapp
    Abstract:

    UNLABELLED Radioiodinated 3(R)-(+)- and 3(S)-(-)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) were prepared and evaluated in rats to investigate the effects of absolute configuration of the 3(beta)-methyl group on myocardial uptake and release kinetics. METHODS The 3(R)-(+)-BMIPP analog was synthesized by initial acylation of a thiophene template with the acid chloride of ethyl 3(R)-methylglutarate. 3(S)-(-)-BMIPP was obtained by separation from the mixture of diastereomeric amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-Alpha-Methylbenzylamine. The amide of synthetic 3(R)-BMIPP prepared from S-(-)-Alpha-Methylbenzylamine was identical to the chromatographically more polar isomer. Free acids were obtained by acid hydrolysis of the amides, fully characterized and then converted to the radioiodinated BMIPP isomers. RESULTS Biodistribution studies in rats with the dual-labeled [(131)I]-3(S)-BMIPP/[(125)I]-3(R)-BMIPP mixture demonstrated greater myocardial uptake of 3(R)-BMIPP compared with the 3(S)-BMIPP isomer [60 min: 3(R)-BMIPP = 4.37 %ID/g; 3(S)-BMIPP = 3.44; p < 0.05; 180 min, 2.31 and 1.78 %ID/G, respectively, p < 0.01], although both isomers had similar myocardial washout curves (5-180 min). Percent ID/g values for other tissues which were examined (blood, lungs, thyroid) were similar. CONCLUSION Higher myocardial uptake of the 3(R)-BMIPP isomer observed in these animal studies may suggest differences in carrier-mediated myocyte uptake of the two isomers. These studies suggest that [(123)I]-3(R)-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3(S)-BMIPP isomer and may thus require reduced injected dose.

  • Nuclear medicine program progress report for quarter ending December 31, 1995
    1995
    Co-Authors: F.f. Knapp, K.r. Ambrose, A.l. Beets, H. Luo, D.w. Mcpherson, S. Mirzadeh, F. Mokler
    Abstract:

    In this report we describe the first resolution of the 3R-(+)-and 3S- ({minus})-methyl BMIPP methyl-branched fatty acid stereoisomers and biodistribution of the radioiodinated isomers in rats to investigate the effects of the configuration of the 3({beta})-methyl group on the organ distribution and myocardial uptake and release kinetics. Synthesesis of 3R-(+)BMIPP was accompanied by initial acylation of the thiophene template with the acid chloride of ethyl 3R- methylglutarate. The amide of the synthetic 3R-BMIPP isomer prepared S-(-)-{Alpha}-Methylbenzylamine exhibited identical spectral and chromatographic properties with the chromatographically more polar isomer (TLC and HPLC) which was separated from the mixture of amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-{Alpha}-Methylbenzylamine. The second less chromatographically polar amide isomer was assigned the 3S-(-)-methyl configuration. The free acids were obtained by acid hydrolysis of the amides and converted to the radioiodinated analogues. While biodistribution studies in separate groups of rats demonstrated greater myocardial uptake of 3R-BMIPP compared with the 3S-isomer values for most other tissues evaluated (blood, lungs, kidneys and thyroid) were similar, whereas the 3S-BMIPP isomer consistently showed higher liver uptake. These results were confirmed in a [l-131]-3S-BMIPP/[l-125]-3R-BMIPP dual label study and both isomers had similar myocardial wash-out curves (5-180 min). These studies suggest that [l-123]-3R-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3S-isomer and thus may require a reduced injected dose compared to racemic BMIPP.

  • Resolution and in vitro and initial in vivo evaluation of isomers of iodine-125-labeled 1-azabicyclo[2.2.2]oct-3-yl Alpha-hydroxy-Alpha-(1-iodo-1-propen-3-yl)-Alpha-phenylacetate: a high-affinity ligand for the muscarinic receptor.
    Journal of medicinal chemistry, 1995
    Co-Authors: D.w. Mcpherson, Carla R. Lambert, Kristi Jahn, V.k. Sood, Robert C. Mcree, B.r. Zeeberg, Richard C. Reba, F.f. Knapp
    Abstract:

    1-Azabicyclo[2.2.2]oct-3-yl Alpha-hydroxy-Alpha-(1-iodo-1-propen-3-yl)- Alpha-phenylacetate (IQNP, 1), is a highly selective ligand for the muscarinic acetylcholinergic receptor (mAChR). There are eight stereoisomers in the racemic mixture. The optical isomers of Alpha-hydroxy-Alpha-phenyl-Alpha-(1-propyn-3-yl)acetic acid were resolved as the Alpha-Methylbenzylamine salts, and the optical isomers of 3-quinuclidinol were resolved as the tartrate salts. The E and Z isomers were prepared by varying the reaction conditions for the stannylation of the triple bond followed by purification utilizing flash column chromatography. In vitro binding assay of the four stereoisomers containing the (R)-(-)-3-quinuclidinyl ester demonstrated that each isomer of 1 bound to mAChR with high affinity. In addition, (E)-(-)-(-)-IQNP demonstrated the highest receptor subtype specificity between the m1 molecular subtype (KD, nM, 0.383 +/- 0.102) and the m2 molecular subtype (29.6 +/- 9.70). In vivo biodistribution studies demonstrated that iodine-125-labeled (E)-(-)-(+)-1 cleared rapidly from the brain and heart. In contrast, iodine-125-labeled (E)-(-)-(-)-, (Z)-(-)-(-)-, and (Z)-(-)-(+)-1 have high uptake and retention in mAChR rich areas of the brain. It was also observed that (E)-(-)-(-)-IQNP demonstrated an apparent subtype selectivity in vivo with retention in M1 (m1, m4) mAChR areas of the rain. In addition, (Z)-(-)-(-)-IQNP also demonstrated significant uptake in tissues containing the M2 (m2) mAChR subtype. These results demonstrate that the iodine-123-labeled analogues of the (E)-(-)-(-)- and (Z)-(-)-(-)-IQNP isomers are attractive candidates for single-photon emission-computed tomographic imaging of cerebral and cardiac mAChR receptor densities.

  • Nuclear medicine program. Progress report for quarter ending June 30, 1995
    1995
    Co-Authors: F.f. Knapp, K.r. Ambrose, A.l. Beets
    Abstract:

    In this report we describe the first synthesis of the (-)(-) and (-)(+) isomers of 1-azabicyclo oct-3-yl {Alpha}-(1-fluoropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetate ({open_quotes}FQNPe{close_quotes}). Earlier studies with the racemic FQNPe mixture had demonstrated high in vitro binding affinity for the muscarinic-cholinergic receptor and showed that pre-treatment of rats with this new agent significantly blocked receptor localization of subsequently injected -Z-(-,-)-IQNP. Because of the potential important use of fluorine-18-labeled analogues for clinical evaluation of changes in muscarinic-cholinergic receptors by positron emission tomography (PET), we have now synthesized the diastereomeric isomers of FQNPe. Multi-gram quantities of ethyl-{Alpha}- (1-chloropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetate were prepared and then saponified into the racemic {Alpha}-(1-chloropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetic acid mixture. The racemic acid was resolved into (-)- and (+)-{Alpha}-(1-chloropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetic acid enantiomers by isolation of the (-) salt of (S-)-(-)-{Alpha}-Methylbenzylamine and the (+) salt of (R)-(+)-{Alpha}-Methylbenzylamine. The resolved (-)- ([{Alpha}]{sub D} = -12.1{degrees}, c = 5.8, chloroform) and (+)-acetic acids ([{Alpha}]{sub D} = + 11.6{degrees}, c = 6.0, chloroform) were fully characterized and then converted to the enantiomeric ethyl-{Alpha}-(1-fluoropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetates by a four-step reaction sequence. The (-)- and (+)-ethyl-{Alpha}-(1-fluoropent-5-yl)-{Alpha}-hydroxy-{Alpha}-phenylacetates were then each transesterified with (-)-quinuclidinol to form the (-)(-) FQNPe and (-)(+) FQNPe diastereomers. These diastereomeric esters will now be evaluated in in vitro studies. The availability of the substratesmore » for preparation of the fluorine-18-labeled enantiomers will now allow evaluation of the radiolabeled compounds in animals.« less

Richard M. Pagni - One of the best experts on this subject based on the ideXlab platform.

  • A study of the liquid and solvent properties of optically active and racemic Alpha-Methylbenzylamine
    The journal of physical chemistry. B, 2007
    Co-Authors: Andrew T. Fischer, Richard M. Pagni, Robert N. Compton
    Abstract:

    Speed-of-sound measurements are reported for RS (racemic) and S liquid α-Methylbenzylamine (MBA) obtained using a modified design of previously published experimental geometry. After correcting for density changes, the resulting isentropic compressibility of the S liquid is found to be 2% larger than that of the RS racemic mixture. These data, along with proton NMR chemical shifts and published partial molar volumes, suggest that the structures of the racemic and optically active liquids are subtly different. The magnitude of the compressibilities and other data such as viscosity and the Kamlet−Taft parameters are consistent with the molecules in the liquids interacting via extensive hydrogen bonding. Cyclohexane, toluene, nitrobenzene, dimethyl sulfoxide, and methanol are completely miscible in MBA, as predicted from their corresponding Hildebrand solubility parameters. Proton NMR, optical rotation, and IR studies were carried out on solutions of the five solutes in MBA as a function of mole fraction. Th...

  • Solvent effects on the optical rotation of (S)-(-)-α-Methylbenzylamine
    The journal of physical chemistry. A, 2006
    Co-Authors: Andrew T. Fischer, Robert N. Compton, Richard M. Pagni
    Abstract:

    The optical rotation of (S)-(-)-Alpha-Methylbenzylamine at 589 nm has been measured in 39 different solvents at five different concentrations: 0.25, 0.50, 1.00, 2.00, and 3.00 M. A correlation of the intrinsic rotations (i.e., extrapolation of specific rotations to zero concentration) with Kamlet's and Taft's solvent parameters (Alpha, beta, and pi) is established. The polarity/polarizability, pi, and solvent acidity, Alpha, terms are found to have a greater effect upon the optical rotation than the basicity of the solvent, beta. The specific rotation for (S)-(-)-Alpha-Methylbenzylamine has been calculated with Gaussian03 using a PCM model (B3LYP aug-cc-pVDZ) for all 39 solvated systems. Comparisons between the experimental and calculated values show the importance of hydrogen bonding on specific rotation.

Robert N. Compton - One of the best experts on this subject based on the ideXlab platform.

  • A study of the liquid and solvent properties of optically active and racemic Alpha-Methylbenzylamine
    The journal of physical chemistry. B, 2007
    Co-Authors: Andrew T. Fischer, Richard M. Pagni, Robert N. Compton
    Abstract:

    Speed-of-sound measurements are reported for RS (racemic) and S liquid α-Methylbenzylamine (MBA) obtained using a modified design of previously published experimental geometry. After correcting for density changes, the resulting isentropic compressibility of the S liquid is found to be 2% larger than that of the RS racemic mixture. These data, along with proton NMR chemical shifts and published partial molar volumes, suggest that the structures of the racemic and optically active liquids are subtly different. The magnitude of the compressibilities and other data such as viscosity and the Kamlet−Taft parameters are consistent with the molecules in the liquids interacting via extensive hydrogen bonding. Cyclohexane, toluene, nitrobenzene, dimethyl sulfoxide, and methanol are completely miscible in MBA, as predicted from their corresponding Hildebrand solubility parameters. Proton NMR, optical rotation, and IR studies were carried out on solutions of the five solutes in MBA as a function of mole fraction. Th...

  • Solvent effects on the optical rotation of (S)-(-)-α-Methylbenzylamine
    The journal of physical chemistry. A, 2006
    Co-Authors: Andrew T. Fischer, Robert N. Compton, Richard M. Pagni
    Abstract:

    The optical rotation of (S)-(-)-Alpha-Methylbenzylamine at 589 nm has been measured in 39 different solvents at five different concentrations: 0.25, 0.50, 1.00, 2.00, and 3.00 M. A correlation of the intrinsic rotations (i.e., extrapolation of specific rotations to zero concentration) with Kamlet's and Taft's solvent parameters (Alpha, beta, and pi) is established. The polarity/polarizability, pi, and solvent acidity, Alpha, terms are found to have a greater effect upon the optical rotation than the basicity of the solvent, beta. The specific rotation for (S)-(-)-Alpha-Methylbenzylamine has been calculated with Gaussian03 using a PCM model (B3LYP aug-cc-pVDZ) for all 39 solvated systems. Comparisons between the experimental and calculated values show the importance of hydrogen bonding on specific rotation.

Andrew T. Fischer - One of the best experts on this subject based on the ideXlab platform.

  • A study of the liquid and solvent properties of optically active and racemic Alpha-Methylbenzylamine
    The journal of physical chemistry. B, 2007
    Co-Authors: Andrew T. Fischer, Richard M. Pagni, Robert N. Compton
    Abstract:

    Speed-of-sound measurements are reported for RS (racemic) and S liquid α-Methylbenzylamine (MBA) obtained using a modified design of previously published experimental geometry. After correcting for density changes, the resulting isentropic compressibility of the S liquid is found to be 2% larger than that of the RS racemic mixture. These data, along with proton NMR chemical shifts and published partial molar volumes, suggest that the structures of the racemic and optically active liquids are subtly different. The magnitude of the compressibilities and other data such as viscosity and the Kamlet−Taft parameters are consistent with the molecules in the liquids interacting via extensive hydrogen bonding. Cyclohexane, toluene, nitrobenzene, dimethyl sulfoxide, and methanol are completely miscible in MBA, as predicted from their corresponding Hildebrand solubility parameters. Proton NMR, optical rotation, and IR studies were carried out on solutions of the five solutes in MBA as a function of mole fraction. Th...

  • Solvent effects on the optical rotation of (S)-(-)-α-Methylbenzylamine
    The journal of physical chemistry. A, 2006
    Co-Authors: Andrew T. Fischer, Robert N. Compton, Richard M. Pagni
    Abstract:

    The optical rotation of (S)-(-)-Alpha-Methylbenzylamine at 589 nm has been measured in 39 different solvents at five different concentrations: 0.25, 0.50, 1.00, 2.00, and 3.00 M. A correlation of the intrinsic rotations (i.e., extrapolation of specific rotations to zero concentration) with Kamlet's and Taft's solvent parameters (Alpha, beta, and pi) is established. The polarity/polarizability, pi, and solvent acidity, Alpha, terms are found to have a greater effect upon the optical rotation than the basicity of the solvent, beta. The specific rotation for (S)-(-)-Alpha-Methylbenzylamine has been calculated with Gaussian03 using a PCM model (B3LYP aug-cc-pVDZ) for all 39 solvated systems. Comparisons between the experimental and calculated values show the importance of hydrogen bonding on specific rotation.

Byung-gee Kim - One of the best experts on this subject based on the ideXlab platform.

  • Kinetic resolution of chiral amines with ω‐transaminase using an enzyme‐membrane reactor
    Biotechnology and bioengineering, 2001
    Co-Authors: Jong Shik Shin, Byung-gee Kim, Andreas Liese, Christian Wandrey
    Abstract:

    A kinetic resolution process for the production of chiral amines was developed using an enzyme-membrane reactor (EMR) and a hollow-fiber membrane contactor with (S)-specific omega-transaminases (omega-TA) from Vibrio fluvialis JS17 and Bacillus thuringiensis JS64. The substrate solution containing racemic amine and pyruvate was recirculated through the EMR and inhibitory ketone product was selectively extracted by the membrane contactor until enantiomeric excess of (R)-amine exceeded 95%. Using the reactor set-up with flat membrane reactor (10-mL working volume), kinetic resolutions of Alpha-Methylbenzylamine (Alpha-MBA) and 1-aminotetralin (200 mM, 50 mL) were carried out. During the operation, concentration of ketone product, i.e., acetophenone or Alpha-tetralone, in a substrate reservoir was maintained below 0.1 mM, suggesting efficient removal of the inhibitory ketone by the membrane contactor. After 47 and 32.5 h of operation using 5 U/mL of enzyme, 98.0 and 95.5% ee of (R)-Alpha-MBA and (R)-1-aminotetralin were obtained at 49.5 and 48.8% of conversion, respectively. A hollow-fiber membrane reactor (39-mL working volume) was used for a preparative-scale kinetic resolution of 1-aminotetralin (200 mM, 1 L). After 133 h of operation, enantiomeric excess reached 95.6% and 14.3 g of (R)-1-aminotetralin was recovered (97.4% of yield). Mathematical modeling of the EMR process including the membrane contactor was performed to evaluate the effect of residence time. The simulation results suggest that residence time should be short to maintain the concentration of the ketone product in EMR sufficiently low so as to decrease conversion per cycle and, in turn, reduce the inhibition of the omega-TA activity.

  • Asymmetric synthesis of chiral amines with ω‐transaminase
    Biotechnology and bioengineering, 1999
    Co-Authors: Jong Shik Shin, Byung-gee Kim
    Abstract:

    The asymmetric synthesis of chiral amines using prochiral ketones was carried out with (S)-specific omega-transaminase (omega-TA) from Vibrio fluvialis JS17. This reaction is inhibited severely by both products, (S)-amine and deaminated ketone. In addition, thermodynamic equilibrium strongly favored the reverse reaction. L-Alanine proved to be the best amino donor based on easy removal of the products. Optimal pH of the reactions with both whole cells and cell-free extract was 7. Amino acceptor reactivities of ketone substrates and reaction profiles of the asymmetric synthesis showed that the initial rate as well as the reaction yield were lower when the resulting (S)-amine from a prochiral ketone substrate was a more reactive amino donor. The yield could be increased dramatically by removing pyruvate, which is a more inhibitory product than (S)-Alpha-Methylbenzylamine [(S)-Alpha-MBA] when acetophenone and L-alanine are used as an amino acceptor and donor, respectively. The removal of pyruvate was carried out by incorporating lactate dehydrogenase (LDH) in cell-free extract or by using whole cells. The whole cell reaction yielded a much better result. When 25 mM benzylacetone and 30 mM acetophenone were used as an amino acceptor with 300 mM L-alanine, 90.2% and 92.1% of the reaction yields after 1 day were obtained with whole cells, respectively. Enantiomeric excesses of both (S)-Alpha-MBA and (S)-1-methyl-3-phenylpropylamine [(S)-MPPA] were all above 99%.

  • Kinetic resolution of α-Methylbenzylamine with ο-transaminase screened from soil microorganisms: Application of a biphasic system to overcome product inhibition
    Biotechnology and bioengineering, 1997
    Co-Authors: Jong Shik Shin, Byung-gee Kim
    Abstract:

    Two microorganisms showing high omicron-transaminase activity (Klebsiella pneumoniae JS2F and Bacillus thuringiensis JS64) were screened by the enrichment method using (S)-Alpha-Methylbenzylamine (Alpha-MBA) as a sole nitrogen source. Optimal carbon and nitrogen sources for enzyme induction and the properties of omicron-transaminases were investigated. omicron-Transaminase from B. thuringiensis JS64 was highly enantioselective (E = 75.3) for (S)-enantiomer of Alpha-MBA and showed remarkable stability. However, omicron-transaminase showed severe product inhibition by acetophenone. An aqueous/organic two-phase system was introduced to overcome this problem. Through solvent screening, cyclohexanone and ethyl acetate were selected as the best organic phases. The acetophenone-extracting capacity of the solvent and the biocompatibility of the solvent to the cell were important determinants in the reaction rate at high concentrations of Alpha-MBA. The reaction rate of omicron-transamination was strongly influenced by the volume ratio of organic phase to aqueous phase as well as agitation speed in the biphasic mixture. Using the optimal volume ratio (Vorg:Vaq = 1:4) in the biphasic system with cyclohexanone, the reaction rate of omicron-transaminase under vigorous mixing conditions increased ninefold compared with that in the monophasic aqueous system. At the same optimal conditions, using whole cells, 500 mM Alpha-MBA could be resolved successfully to above 95% enantiomeric excess of (R)-Alpha-MBA with ca. 51% conversion. (c) 1997 John Wiley & Sons, Inc. Biotechnol Bioeng 55: 348-358, 1997.