The GABAA receptor is very widely distributed in the brain and spinal cord and the major inhibitory receptor in the central nervous system (CNS). In the spinal cord the GABA receptors are involved in motoric control. In the thalamus, GABA acts at the initiation and maintenance of sleep. Pharmacologically, shortly summarized, these receptors can mediate the sedative effects of benzodiazepines (diazepam), are connected with an anxiolytic function or can have a muscle relaxant effect. For a brief review, see:
The GABAA receptor is very widely distributed in the brain and spinal cord and the major inhibitory receptor in the central nervous system (CNS). In the spinal cord the GABA receptors are involved in motoric control. In the thalamus, GABA acts at the initiation and maintenance of sleep. Pharmacologically, shortly summarized, these receptors can mediate the sedative effects of benzodiazepines (diazepam), are connected with an anxiolytic function or can have a muscle relaxant effect. For a brief review, see:. Chebib M., and Johnston G.A.R. Clin. Exp. Pharmacol. Physiol. 26 (1999) 937-940
Most interestingly GABA is synthesized by means of glutamate decarboxylase (GAD) from glutamate. So in one step the main excitatory neurotransmitter is converted to most important inhibitory neurotransmitter, or in other words the γ-aminobutyric acid (GABA) can be seen as the biogenic amine of the glutamic acid.
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Hossain M.A., and Schneider H.-J. J. Am. Chem. Soc. 120 (1998) 11208-11209
Breccia P., Van Gool M., Perez-Fernandez R., Marti{dotless}n-Santamari{dotless} S., Gago F., Prados P., and de Mendoza J. J. Am. Chem. Soc. 125 (2003) 8270-8284
Syntheses examples for guanidines via carbodiimides
Syntheses examples for guanidines via carbodiimides. Isobe T., Fukuda K., Yamaguchi K., Seki H., Tokunaga T., and Ishikawa T. J. Org. Chem. 65 (2000) 7779-7785
Compound 14a was prepared on an alternative route using a twofold Cbz-protected analogue of compound 10 and final deprotection by hydrogenation yielding the free base
Compound 14a was prepared on an alternative route using a twofold Cbz-protected analogue of compound 10 and final deprotection by hydrogenation yielding the free base. Wiskur S.L., Lavigne J.J., Metzger A., Tobey S.L., Lynch V., and Anslyn E.V. Chem.-Eur. J. 10 (2004) 3792-3804
The amide position can be deprotonated more easily. The propargyl-substituent is region selectively introduced at one of the Boc-protected nitrogen atoms.
4 as the reference compound (Φ=0.546). The solution was degassed and measured in a closed, nitrogen flushed cuvette with septum.
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All compounds show due to their close structural relationship very similar photophysical properties: ε (nm)=220 (27,000-30,000), 270 (7000-8500).
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a values of the tertiary amine in the crown ether in dependency on the spacer were evaluated by titration with perchloric acid (see Supplementary data). The aliphatic amines possess about the same basicity and are all between 5.6 and 6; only the aromatic substituent differs slightly with a value of 6.6.
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To prevent a potential cleavage of the methyl esters and decomposition of the acetyl-guanidine moiety, the measurements are restricted to the range pH>5 to max pH=10.
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a value of the guanidinium moiety may vary depending on the adjacent group effects, in general it will be lowered by aromatic acyl>aliphatic acyl>phenyl>alkyl
a value of the guanidinium moiety may vary depending on the adjacent group effects, in general it will be lowered by aromatic acyl>aliphatic acyl>phenyl>alkyl. Schug K.A., and Lindner W. Chem. Rev. 105 (2005) 67-113
a of aromatic acyl-guanidines is between 6 and 7 [see also Ref. 35], of aliphatic examples it is between 7 and 8. The alkylated or unsubstituted guanidines with about five orders of magnitude higher values can be assumed as always protonated under the given conditions
a of aromatic acyl-guanidines is between 6 and 7 [see also Ref. 35], of aliphatic examples it is between 7 and 8. The alkylated or unsubstituted guanidines with about five orders of magnitude higher values can be assumed as always protonated under the given conditions
1H NMR (300 MHz, MeOD) [ppm]=1.48 (m, 2H), 1.70 (m, 2H), 1.84 (m, 2H), 2.02 (s, 3H), 2.91 (m, 2H), 3.91 (s, 3H), 4.38 (m, 1H); 1 equiv of 0.01 M aqueous hydrochloric acid was added and the resulting salt was lyophilized before it was used for the measurement.
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Examples for guanidine binding by crown ethers smaller than 27-crown-9
Examples for guanidine binding by crown ethers smaller than 27-crown-9. Gawley R.E., Pinet S., Cardona C.M., Datta P.K., Ren T., Guida W.C., Nydick J., and Leblanc R.M. J. Am. Chem. Soc. 124 (2002) 13448-13453
Tryptophan was excluded, as it absorbs in the same range as the crown ether fluorophore. The binding of tyrosine was not investigated; it is not sufficiently soluble under the experimental conditions.
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Solvatochromatic effects may lead to additional changes in the emission.
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84982343508
The crown ether guanidinium combinations with thioureido chain or with triazole rings coordinate mercury ions weakly. Stable mercury compounds of triazoles are known
The crown ether guanidinium combinations with thioureido chain or with triazole rings coordinate mercury ions weakly. Stable mercury compounds of triazoles are known. Müller E., and Meier H. Liebigs Ann. Chem. 716 (1968) 11-18
Most acetyl-guanidines are comparable in their stability with esters. Acyl-guanidines are in general isolable compounds and can be stored as salts in non-nucleophilic solvents over a long time without any decomposition. A possible intramolecular nucleophilic attack can accelerate the decomposition reaction enormously The acyl-guanidines proved to be stable for at least several days in solution. No different behaviour was observed if the screenings are repeated after 2-3 days. No strong nucleophile is present and the pH of the measurement never exceeded the range between 6 and 8
Most acetyl-guanidines are comparable in their stability with esters. Acyl-guanidines are in general isolable compounds and can be stored as salts in non-nucleophilic solvents over a long time without any decomposition. A possible intramolecular nucleophilic attack can accelerate the decomposition reaction enormously. Brennauer A., Keller M., Freund M., Bernhard G., and Buschauer A. Tetrahedron Lett. 48 (2007) 6996-6999 The acyl-guanidines proved to be stable for at least several days in solution. No different behaviour was observed if the screenings are repeated after 2-3 days. No strong nucleophile is present and the pH of the measurement never exceeded the range between 6 and 8
The combination Glu-Lys as in the dipeptide is found in functional regions of many important peptides as ubiquitin
The combination Glu-Lys as in the dipeptide is found in functional regions of many important peptides as ubiquitin. Pickart C.M., and Eddins M.J. Biochim. Biophys. Acta 1695 (2004) 55-72
It is highly conserved in nearly all human endorphins, for examples see
It is highly conserved in nearly all human endorphins, for examples see. Ling N., Burgus R., and Guillemin R. Proc. Natl. Acad. Sci. U.S.A. 73 (1976) 3942-3946
Energy minimization molecular modeling studies with the aid of the program package Spartan were used to obtain structural information for various receptor amino acid or peptide complexes and served as a basis to explain the observed differences in the binding constant. The depicted schemes are illustrative pictures, the modeling results can be found in the Supplementary data.
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Reactions like peptide coupling, thiourea- or urea synthesis or the versatile Huisgen cycloaddition are especially suitable for the assembly. A broad variety of synthetic prescriptions, which are compatible with almost any substituent, are existent. For example
Reactions like peptide coupling, thiourea- or urea synthesis or the versatile Huisgen cycloaddition are especially suitable for the assembly. A broad variety of synthetic prescriptions, which are compatible with almost any substituent, are existent. For example. Merrifield R.B. J. Am. Chem. Soc. 85 (1963) 2149-2154
The analog receptors carrying one acetyl group were prepared after a similar procedure (GP IV). The 1-Boc-3-acetyl-2-methyl-2-isothiourea (145 mg, 0.5 mmol) was used instead. The well stirred solution was heated to 40 °C under nitrogen atmosphere and held at this temperature over night. The workup is the same.
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Amino acids in their zwitterionic form are not sufficiently soluble in pure methanol, therefore the measurements have to be conducted in aqueous mixtures.
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A pH electrode for methanolic solutions was used and calibrated once a day.
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Salt addition is avoided; it increases the polarity of the solvent systems and interferes with the guanidinium binding.
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