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Glutamate and aspartate agonists structurally related to ibotenic acid (1981)

Honoré, Tage ; Krogsgaard-Larsen, Povl ; Hansen, Jan J. ; [et al.]

Springer

Molecular and cellular biochemistry 38 (1981), S. 123-1281

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ISSN: 1573-4919

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Summary This mini-review describes a noval class of excitatory heterocyclic amino acid. The selective interactions of these synthetic amino acids with the central glutamic acid (GLU) and aspartic acid (ASP) receptors have been established on the basis of microelectrophoretic techniques using glutamic acid diethyl ester (GDEE) and α-aminoadipic acid (a-AA) as selective antagonists for GLU and ASP, respectively. The parent compound., ibotenic acid (IBO) preferentially activates ASP receptors, but elongation of the side chain of IBO afforded homoibotenic acid (homo-IBO), a GLU agonist. The introduction of bulky substituents into the heterocyclic ring of homo-IBO resulted in a dramatic increase in potency. Alteration of the position of the side chain in IBO to give α-amino-5-methyl-3-hydroxy-4-isoxazoleacetic acid (AMAA), preserved the ASP agonism. However, elongation of the side chain of AMAA gave α-amino-5-methyl-3-hydroxy-4-isoxazolepropionic acid (AMPA), which is a very powerful neuronal excitant with selective interaction with the GLU receptors. None of the new compounds are inhibitors of the binding of 3H-kainic acid (3H-KAIN) to rat brain membranes, indicating that the mechanism of action of these compounds is different from that of the neurotoxic compound KAIN. The described compounds may be important tools in future investigations of the physiological role and the mechanism of action of ASP and GLU in the central nervous system (CNS).

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF00235691

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GABAB antagonists: Resolution, absolute stereochemistry, and pharmacology of (R)- and (S)-phaclofen (1994)

Frydenvang, Karla ; Hansen, Jan J. ; Krogsgaard-Larsen, Povl ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 6 (1994), S. 583-589

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ISSN: 0899-0042

Keywords: chiral HPLC ; resolution ; absolute configuration ; X-ray analysis ; GABAB antagonist ; GABAB receptor affinity ; phaclofen ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chromatographic techniques. The absolute stereochemistry of (-)-(R)-phaclofen was established by X-ray crystallographic analysis. (-)-(R)-Phaclofen was shown to inhibit the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 ± 13 μM), whereas (+)-(S)-phaclofen was inactive in this binding assay (IC50 〉 1000 μM). (-)-(R)-Phaclofen (200 μM) was equipotent with (RS)-phaclofen (400 μM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 μM) was inactive. The structural similarity of the agonist (R)-baclofen and the antagonist (-)-(R)-phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups. © 1994 Wiley-Liss, Inc.

Additional Material: 4 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530060712

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GABAA agonists: Resolution and pharmacology of (+)- and (-)-isoguvacine oxide (1995)

Frølund, Bente ; Jeppesen, Lone ; Krogsgaard-Larsen, Povl ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Chirality 7 (1995), S. 434-438

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ISSN: 0899-0042

Keywords: chiral HPLC ; resolution ; enantiomeric purity ; GABAA receptor affinity ; GABAA agonist ; benzodiazepine stimulation ; Chemistry ; Organic Chemistry

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Chemistry and Pharmacology

Notes: (3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABAA receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABAA receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyloxycarbonyl)-3,4-epoxypiperidine-4-carboxylate (1) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [3H]GABA to GABAB receptor sites (IC50 〉 100 μM), (+)-isoguvacine oxide (IC50 = 0.20 ± 0.03 μM) and (-)-isoguvacine oxide (IC50 = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [3H]GABA to GABAA receptor sites. Furthermore, (+)-isoguvacine oxide (EC50 = 6 μM; 33% relative efficacy) and (-)-isoguvacine oxide (EC50 = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [3H]diazepam to the GABAA receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABAA agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABAA recognition site(s), derived from extensive structure - activity studies on GABAA agonists. Thus, the model of the GABAA recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABAA agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley-Liss, Inc.

Additional Material: 3 Ill.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1002/chir.530070608

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