Povl Krogsgaard-larsen - Academia.edu (original) (raw)

Papers by Povl Krogsgaard-larsen

Research paper thumbnail of Characterization of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling

Molecular Neuropharmacology, 2004

... of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling Bente... more ... of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling Bente Frølund, Anne T. Jørgensen, Tommy Liljefors, Martin ... 3. Krogsgaard-Larsen, P., Johnston, GAR, Curtis, DR, Game, CJA, and McCulloch, R. M.(1975) Structure and biological ...

Research paper thumbnail of Synthesis of 1-Acyl-3-piperidones and Ring Expansion of Methyl 3-Oxopiperidine-1-carboxylate with Ethyl Diazoacetate

Acta Chemica Scandinavica, 1976

Research paper thumbnail of Potential GABA Uptake Inhibitors. Synthesis and Relative Stereochemistry of Some Aminopiperidinecarboxylic Acids

Acta Chemica Scandinavica, 1980

Research paper thumbnail of Structural Analogues of GABA. Synthesis of 5-Aminomethyl-3-isothiazolol (Thiomuscimol)

Acta Chemica Scandinavica, 1976

Research paper thumbnail of Syntheses of Some Cyclic Amino Acids Structurally Related to the GABA Analogue Homo-beta-Proline

Acta Chemica Scandinavica, 1982

Research paper thumbnail of Unambiguous synthesis of 1-methyl-3-hydroxypyrazoles

Tetrahedron, 1998

2, 3-Dihydropyrazolo [3, 2-b] oxazoles were used as intermediates in a new method for preparation... more 2, 3-Dihydropyrazolo [3, 2-b] oxazoles were used as intermediates in a new method for preparation of N1-methyl-3-hydroxypyrazoles. Synthesis of this bicyclic system was achieved either by alkylation of 3-hydroxypyrazole with 1, 2-dibromoethane or, with better ...

Research paper thumbnail of Glutamate receptors and new glutamate agonists

Trends in Pharmacological Sciences, 1983

... 3 In: G. DiChiara and GL Gessa, Editors, Glutamate as a Neurotransmitter, Raven Press, New Yo... more ... 3 In: G. DiChiara and GL Gessa, Editors, Glutamate as a Neurotransmitter, Raven Press, New York (1981). 4 In: PJ Roberts, J. Storm-Mathisen and GAR Johnston, Editors, Glutamate: Transmitter in the Central Nervous System, John Wiley & Sons, Chichester, New York ...

Research paper thumbnail of Preparation of Novel Piperidine Phosphinic Acid Analogues of the Inhibitory Neurotransmitter γ-Aminobutyric Acid (GABA)

Phosphorus, Sulfur, and Silicon and the Related Elements, 1999

Research paper thumbnail of Metabotropic and ionotropic GABA receptors and receptor ligands

Pharmacological Research, 1995

Research paper thumbnail of Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Medicinal Research Reviews, 2009

(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous... more (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists.

Research paper thumbnail of gamma.-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects

Journal of Medicinal Chemistry, 1981

In recent years there has been a rapidly increasing interest in the pharmacology of the central a... more In recent years there has been a rapidly increasing interest in the pharmacology of the central amino acid neurotransmitters, and the complicity of y-aminobutyric acid (GABA) in certain neurological and psychiatric diseases has brought this amino acid into focus. The development of the pharmacology of a central amino acid neurotransmitter system involves many problems and represents a great challenge to medicinal chemists. The present article will discuss strategies for pharmacological interventions in the GABA system and for the design of agents with specific actions on GABA synaptic mechanisms. GABA: A Central Inhibitory Neurotransmitter Since the demonstration of the presence of GABA in the mammalian central nervous system (CNS) some 30 years ago, the physiology and biochemistry of the GABA system has been extensively studied.l+ GABA has a ubiquitous distribution in the CNS, and GABA fulfills7 the main criteria* established for the identification of an inhibitory neurotransmitter: (1) GABA is synthesized and stored within a limited population of nerve terminals, (2) the release of GABA from CNS tissue preparations can be induced by electric stimulation in vitro under approximate physiological conditions and in vivo by impulses in particular neuronal pathways, (3) the depressant action of GABA applied on single neurons mimics the effects of the (1) E.

Research paper thumbnail of Neuroactive Polyamine Wasp Toxins:  Nuclear Magnetic Resonance Spectroscopic Analysis of the Protolytic Properties of Philanthotoxin-343

Journal of Medicinal Chemistry, 1996

Acid-base properties (pK a values and proton distribution patterns) of philanthotoxin-343 (PhTX-3... more Acid-base properties (pK a values and proton distribution patterns) of philanthotoxin-343 (PhTX-343) were investigated by 1 H and 13 C NMR titration. Chemical shift data and the total ionization shifts were used to assign carbon atoms of the polyamine chain. Nonlinear analysis of the 13 C NMR titration curves gave four pK a values (pK 1 8.5, pK 2 9.5, pK 3 10.4, pK 4 11.4) and the intrinsic chemical shifts of the non-, mono-, di-, tri-, and tetraprotonated forms. The changes of intrinsic chemical shifts enabled analysis of the deprotonation sequence of fully protonated PhTX-343. The results of analysis of the 13 C NMR titration curves were supported by 1 H NMR data obtained from two-dimensional 1 H, 13 C chemical shift correlation experiments. Thus, the first deprotonation mainly takes place at the inner amino group. The phenol group is deprotonated in the second and third deprotonation steps. The preferential deprotonation of the inner amino group is also apparent in the diprotonated form. The monoprotonated form carries a practically fully ionized phenol group and the proton shared between the three amino groups. This characteristic is in agreement with existing data on polyamines. At physiological pH, the tetraprotonated form of PhTX-343 predominates, but the proportion of the triprotonated form becomes significant at low ionic strength. The terminal, primary amino group, which has been shown to be essential for biological activity, remains practically fully protonated at biologically relevant pH values, and this charge is likely to participate in the receptor-binding event. Protonation of the central amino group does not appear to be necessary for biological activity.

Research paper thumbnail of Sequence and Expression Pattern of a Novel Human Orphan G-Protein-Coupled Receptor, GPRC5B, a Family C Receptor with a Short Amino-Terminal Domain

Genomics, 2000

Query of GenBank with the amino acid sequence of human metabotropic glutamate receptor subtype 2 ... more Query of GenBank with the amino acid sequence of human metabotropic glutamate receptor subtype 2 (mGluR2) identified a predicted gene product of unknown function on BAC clone CIT987SK-A-69G12 (located on chromosome band 16p12) as a homologous protein. The transcript, entitled GPRC5B, was cloned from an expressed sequence tag clone that contained the entire open reading frame of the transcript encoding a protein of 395 amino acids. Analysis of the protein sequence reveal that GPRC5B contains a signal peptide and seven transmembrane ␣-helices, which is a hallmark of G-protein-coupled receptors (GPCRs). GPRC5B displays homology to retinoic acid-inducible gene 1 (RAIG1, 33% sequence identity) and to several family C (mGluR-like) GPCRs (20-25% sequence identity). Both RAIG1 and GPRC5B have short extracellular amino-terminal domains (ATDs) that contrast the very long ATDs characterizing the receptors currently assigned to family C. However, our results strongly indicate that RAIG1 and GPRC5B form a new subgroup of family C characterized by short ATDs. GPRC5B mRNA is widely expressed in peripheral and central tissues with highest abundance in kidney, pancreas, and testis. This mRNA expression pattern is markedly different from that of RAIG1, which shows a slightly more restricted expression pattern with highest abundance in lung tissue.

Research paper thumbnail of Pharmacological characterization of homobaclofen on wild type and mutant GABAB1b receptors coexpressed with the GABAB2 receptor

European Journal of Pharmacology, 2001

Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) ... more Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies between the data obtained in this study and those from the guinea pig ileum model could be ascribed to differences in amino acid sequence or receptor splicing of GABA(B) receptors between the two species. Another explanation for the observation is the possible existence of a novel yet uncloned GABA(B) receptor in guinea pig ileum.

Research paper thumbnail of Differentiation of in vivo effects of AMPA and NMDA receptor ligands using drug discrimination methods and convulsant/anticonvulsant activity

European Journal of Pharmacology, 1995

The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-... more The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-aspartic acid) in rats have been characterized. It is suggested that the cues are mediated by separate mechanisms in the central nervous system. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, and is inhibited by the AMPA receptor antagonist (R)-APPA ((R)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor antagonist ATOA ((RS)-2-amino-3-(3-carboxymethoxy-5-tert-butylisoxazol-4-yl)propio nic acid) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-yl)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which is believed not to penetrate the blood-brain barrier. In contrast, ATPA does not generalize to the NMDA cue, which is mimicked by some NMDA receptor agonists (tetrazol-5-yl-glycine and AMAA ((RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA receptor antagonist CPP. Highly potent convulsant activity was demonstrated in mice with all AMPA and NMDA receptor agonists after intracerebroventricular (i.c.v.) injection, whereas weaker or no effects were found after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetrazol-5-yl-glycine had a potent effect after s.c. administration. I.c.v. ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA or NMDA, while (R)-APPA was ineffective. These results indicate that there are differences in the structure-activity relations in the drug discrimination and convulsant/anticonvulsant models, even when effects after i.c.v. and s.c. injection are taken into consideration. The convulsion models are rapid tests which can give an indication of central nervous system penetration, but are less pharmacologically specific with respect to differentiation between AMPA and NMDA ligands where cue models demonstrate clear differences in effects of ligands with selectivity for receptor subtypes.

Research paper thumbnail of Pharmacological studies of interactions between benzodiazepines and GABA receptors

Brain Research Bulletin, 1980

Research paper thumbnail of Bioisosterically modified dipeptide excitatory amino acid receptor antagonists containing 3-oxygenated isothiazole ring systems

Bioorganic & Medicinal Chemistry, 1997

The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the s... more The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the selective NMDA antagonist, 2, in which a 3-isothiazolone unit is a bioisosteric analogue of the peptide bond of the NMDA antagonist, gamma-(R)-Glu-Gly. The isomeric 3-oxygenated isothiazole amino acid, 3, and the corresponding isothiazole phosphono amino acid 4 were also synthesized, and were shown to be selective AMPA receptor antagonists. Compound 1, in which the peptide bond of gamma-(R)-Glu-Gly is replaced by an ester group, was synthesized and shown to be unstable in the test buffer system.

Research paper thumbnail of Deuterium labelling of the GABA agonist thiomuscimol

Journal of Labelled Compounds and Radiopharmaceuticals, 1984

... 1. 2 . 3 . 4 . 5 . 6 . 7. 8 . 9 . 10. 11. 1 2 * REFERENCES Roberts, E., Chase, TN and Tower, ... more ... 1. 2 . 3 . 4 . 5 . 6 . 7. 8 . 9 . 10. 11. 1 2 * REFERENCES Roberts, E., Chase, TN and Tower, DB Eds., GABA in Nervous System Function, Raven Press, New York 1976 Krogsgaard-Larsen, P., Scheel-Kruger, J. and Kofod, H. Eds., GABA-Neurotransmitters. Pharmacochemical, Bio-...

Research paper thumbnail of (−)-( R )-5,5-Dimethylmorpholinyl-2-acetic Acid Ethyl Ester Hydrochloride, C 10 H 20 NO 3 + .Cl −

Acta Crystallographica Section C Crystal Structure Communications, 1997

Research paper thumbnail of Organic Hydroxylamine Derivatives. IX. Structural Analogues of GABA of the Isoxazole Enol-betaine Type. Improved Synthesis and the Crystal Structure of 3-Hydroxy-5-(2-aminoethyl)isoxazole Zwitterion (Homomuscimol)

Acta Chemica Scandinavica, 1974

Research paper thumbnail of Characterization of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling

Molecular Neuropharmacology, 2004

... of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling Bente... more ... of the GABAA Receptor Recognition Site Through Ligand Design and Pharmacophore Modeling Bente Frølund, Anne T. Jørgensen, Tommy Liljefors, Martin ... 3. Krogsgaard-Larsen, P., Johnston, GAR, Curtis, DR, Game, CJA, and McCulloch, R. M.(1975) Structure and biological ...

Research paper thumbnail of Synthesis of 1-Acyl-3-piperidones and Ring Expansion of Methyl 3-Oxopiperidine-1-carboxylate with Ethyl Diazoacetate

Acta Chemica Scandinavica, 1976

Research paper thumbnail of Potential GABA Uptake Inhibitors. Synthesis and Relative Stereochemistry of Some Aminopiperidinecarboxylic Acids

Acta Chemica Scandinavica, 1980

Research paper thumbnail of Structural Analogues of GABA. Synthesis of 5-Aminomethyl-3-isothiazolol (Thiomuscimol)

Acta Chemica Scandinavica, 1976

Research paper thumbnail of Syntheses of Some Cyclic Amino Acids Structurally Related to the GABA Analogue Homo-beta-Proline

Acta Chemica Scandinavica, 1982

Research paper thumbnail of Unambiguous synthesis of 1-methyl-3-hydroxypyrazoles

Tetrahedron, 1998

2, 3-Dihydropyrazolo [3, 2-b] oxazoles were used as intermediates in a new method for preparation... more 2, 3-Dihydropyrazolo [3, 2-b] oxazoles were used as intermediates in a new method for preparation of N1-methyl-3-hydroxypyrazoles. Synthesis of this bicyclic system was achieved either by alkylation of 3-hydroxypyrazole with 1, 2-dibromoethane or, with better ...

Research paper thumbnail of Glutamate receptors and new glutamate agonists

Trends in Pharmacological Sciences, 1983

... 3 In: G. DiChiara and GL Gessa, Editors, Glutamate as a Neurotransmitter, Raven Press, New Yo... more ... 3 In: G. DiChiara and GL Gessa, Editors, Glutamate as a Neurotransmitter, Raven Press, New York (1981). 4 In: PJ Roberts, J. Storm-Mathisen and GAR Johnston, Editors, Glutamate: Transmitter in the Central Nervous System, John Wiley & Sons, Chichester, New York ...

Research paper thumbnail of Preparation of Novel Piperidine Phosphinic Acid Analogues of the Inhibitory Neurotransmitter γ-Aminobutyric Acid (GABA)

Phosphorus, Sulfur, and Silicon and the Related Elements, 1999

Research paper thumbnail of Metabotropic and ionotropic GABA receptors and receptor ligands

Pharmacological Research, 1995

Research paper thumbnail of Subtype selective kainic acid receptor agonists: Discovery and approaches to rational design

Medicinal Research Reviews, 2009

(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous... more (S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in the mammalian central nervous system, activating the plethora of glutamate receptors (GluRs). In broad lines, the GluRs are divided into two major classes: the ionotropic Glu receptors (iGluRs) and the metabotropic Glu receptors (mGluRs). Within the iGluRs, five subtypes (KA1, KA2, iGluR5-7) show high affinity and express full agonist activity upon binding of the naturally occurring amino acid kainic acid (KA). Thus these receptors have been named the KA receptors. This review describes all-to our knowledge-published KA receptor agonists. In total, over 100 compounds are described by means of chemical structure and available pharmacological data. With this perspective review, it is our intention to ignite and stimulate inspiration for future design and synthesis of novel subtype selective KA receptor agonists.

Research paper thumbnail of gamma.-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects

Journal of Medicinal Chemistry, 1981

In recent years there has been a rapidly increasing interest in the pharmacology of the central a... more In recent years there has been a rapidly increasing interest in the pharmacology of the central amino acid neurotransmitters, and the complicity of y-aminobutyric acid (GABA) in certain neurological and psychiatric diseases has brought this amino acid into focus. The development of the pharmacology of a central amino acid neurotransmitter system involves many problems and represents a great challenge to medicinal chemists. The present article will discuss strategies for pharmacological interventions in the GABA system and for the design of agents with specific actions on GABA synaptic mechanisms. GABA: A Central Inhibitory Neurotransmitter Since the demonstration of the presence of GABA in the mammalian central nervous system (CNS) some 30 years ago, the physiology and biochemistry of the GABA system has been extensively studied.l+ GABA has a ubiquitous distribution in the CNS, and GABA fulfills7 the main criteria* established for the identification of an inhibitory neurotransmitter: (1) GABA is synthesized and stored within a limited population of nerve terminals, (2) the release of GABA from CNS tissue preparations can be induced by electric stimulation in vitro under approximate physiological conditions and in vivo by impulses in particular neuronal pathways, (3) the depressant action of GABA applied on single neurons mimics the effects of the (1) E.

Research paper thumbnail of Neuroactive Polyamine Wasp Toxins:  Nuclear Magnetic Resonance Spectroscopic Analysis of the Protolytic Properties of Philanthotoxin-343

Journal of Medicinal Chemistry, 1996

Acid-base properties (pK a values and proton distribution patterns) of philanthotoxin-343 (PhTX-3... more Acid-base properties (pK a values and proton distribution patterns) of philanthotoxin-343 (PhTX-343) were investigated by 1 H and 13 C NMR titration. Chemical shift data and the total ionization shifts were used to assign carbon atoms of the polyamine chain. Nonlinear analysis of the 13 C NMR titration curves gave four pK a values (pK 1 8.5, pK 2 9.5, pK 3 10.4, pK 4 11.4) and the intrinsic chemical shifts of the non-, mono-, di-, tri-, and tetraprotonated forms. The changes of intrinsic chemical shifts enabled analysis of the deprotonation sequence of fully protonated PhTX-343. The results of analysis of the 13 C NMR titration curves were supported by 1 H NMR data obtained from two-dimensional 1 H, 13 C chemical shift correlation experiments. Thus, the first deprotonation mainly takes place at the inner amino group. The phenol group is deprotonated in the second and third deprotonation steps. The preferential deprotonation of the inner amino group is also apparent in the diprotonated form. The monoprotonated form carries a practically fully ionized phenol group and the proton shared between the three amino groups. This characteristic is in agreement with existing data on polyamines. At physiological pH, the tetraprotonated form of PhTX-343 predominates, but the proportion of the triprotonated form becomes significant at low ionic strength. The terminal, primary amino group, which has been shown to be essential for biological activity, remains practically fully protonated at biologically relevant pH values, and this charge is likely to participate in the receptor-binding event. Protonation of the central amino group does not appear to be necessary for biological activity.

Research paper thumbnail of Sequence and Expression Pattern of a Novel Human Orphan G-Protein-Coupled Receptor, GPRC5B, a Family C Receptor with a Short Amino-Terminal Domain

Genomics, 2000

Query of GenBank with the amino acid sequence of human metabotropic glutamate receptor subtype 2 ... more Query of GenBank with the amino acid sequence of human metabotropic glutamate receptor subtype 2 (mGluR2) identified a predicted gene product of unknown function on BAC clone CIT987SK-A-69G12 (located on chromosome band 16p12) as a homologous protein. The transcript, entitled GPRC5B, was cloned from an expressed sequence tag clone that contained the entire open reading frame of the transcript encoding a protein of 395 amino acids. Analysis of the protein sequence reveal that GPRC5B contains a signal peptide and seven transmembrane ␣-helices, which is a hallmark of G-protein-coupled receptors (GPCRs). GPRC5B displays homology to retinoic acid-inducible gene 1 (RAIG1, 33% sequence identity) and to several family C (mGluR-like) GPCRs (20-25% sequence identity). Both RAIG1 and GPRC5B have short extracellular amino-terminal domains (ATDs) that contrast the very long ATDs characterizing the receptors currently assigned to family C. However, our results strongly indicate that RAIG1 and GPRC5B form a new subgroup of family C characterized by short ATDs. GPRC5B mRNA is widely expressed in peripheral and central tissues with highest abundance in kidney, pancreas, and testis. This mRNA expression pattern is markedly different from that of RAIG1, which shows a slightly more restricted expression pattern with highest abundance in lung tissue.

Research paper thumbnail of Pharmacological characterization of homobaclofen on wild type and mutant GABAB1b receptors coexpressed with the GABAB2 receptor

European Journal of Pharmacology, 2001

Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) ... more Homobaclofen (5-amino-3-(4-chlorophenyl) pentanoic acid) is a homologue of the classical GABA(B) receptor agonist baclofen. In a recent study, the two enantiomers of this compound were tested in a GABA(B) receptor selective [3H]gamma-aminobutyric acid ([3H]GABA) binding assay using rat brain homogenate and in an assay of electrically induced contractions of guinea pig ileum. The results from the two tissues did, however, not correlate very well, and in order to further investigate these discrepancies, we have pharmacologically characterized these enantiomers on recombinant wild type and mutant rat GABA(B)1b receptors coexpressed with rat GABA(B)2 receptors. The results from this study correlate nicely with the binding data from rat brain. (R)-Homobaclofen was shown to act like (R)-baclofen albeit with 20-fold less potency, and (S)-homobaclofen was inactive on the receptor. The discrepancies between the data obtained in this study and those from the guinea pig ileum model could be ascribed to differences in amino acid sequence or receptor splicing of GABA(B) receptors between the two species. Another explanation for the observation is the possible existence of a novel yet uncloned GABA(B) receptor in guinea pig ileum.

Research paper thumbnail of Differentiation of in vivo effects of AMPA and NMDA receptor ligands using drug discrimination methods and convulsant/anticonvulsant activity

European Journal of Pharmacology, 1995

The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-... more The discriminative stimulus properties of the AMPA ((RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid) receptor agonist ATPA ((RS)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propionic acid) and NMDA (N-methyl-D-aspartic acid) in rats have been characterized. It is suggested that the cues are mediated by separate mechanisms in the central nervous system. The ATPA cue is not mimicked by NMDA or an NMDA receptor agonist, and is inhibited by the AMPA receptor antagonist (R)-APPA ((R)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid) but not the AMPA receptor antagonist ATOA ((RS)-2-amino-3-(3-carboxymethoxy-5-tert-butylisoxazol-4-yl)propio nic acid) or the NMDA receptor antagonist CPP ((RS)-3-(2-carboxypiperazin-4-yl)propyl)phosphonic acid). The ATPA cue is not mimicked by AMPA which is believed not to penetrate the blood-brain barrier. In contrast, ATPA does not generalize to the NMDA cue, which is mimicked by some NMDA receptor agonists (tetrazol-5-yl-glycine and AMAA ((RS)-2-amino-2-(3-hydroxy-5-methylisoxazol-4-yl)acetic acid)) and is inhibited by the NMDA receptor antagonist CPP. Highly potent convulsant activity was demonstrated in mice with all AMPA and NMDA receptor agonists after intracerebroventricular (i.c.v.) injection, whereas weaker or no effects were found after subcutaneous (s.c.) or intravenous injection. Only (RS)-tetrazol-5-yl-glycine had a potent effect after s.c. administration. I.c.v. ATOA and CPP inhibited convulsions induced by i.c.v. injection of AMPA or NMDA, while (R)-APPA was ineffective. These results indicate that there are differences in the structure-activity relations in the drug discrimination and convulsant/anticonvulsant models, even when effects after i.c.v. and s.c. injection are taken into consideration. The convulsion models are rapid tests which can give an indication of central nervous system penetration, but are less pharmacologically specific with respect to differentiation between AMPA and NMDA ligands where cue models demonstrate clear differences in effects of ligands with selectivity for receptor subtypes.

Research paper thumbnail of Pharmacological studies of interactions between benzodiazepines and GABA receptors

Brain Research Bulletin, 1980

Research paper thumbnail of Bioisosterically modified dipeptide excitatory amino acid receptor antagonists containing 3-oxygenated isothiazole ring systems

Bioorganic & Medicinal Chemistry, 1997

The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the s... more The AMPA receptor agonist Thio-AMPA, the 3-isothiazolol analogue of AMPA was converted into the selective NMDA antagonist, 2, in which a 3-isothiazolone unit is a bioisosteric analogue of the peptide bond of the NMDA antagonist, gamma-(R)-Glu-Gly. The isomeric 3-oxygenated isothiazole amino acid, 3, and the corresponding isothiazole phosphono amino acid 4 were also synthesized, and were shown to be selective AMPA receptor antagonists. Compound 1, in which the peptide bond of gamma-(R)-Glu-Gly is replaced by an ester group, was synthesized and shown to be unstable in the test buffer system.

Research paper thumbnail of Deuterium labelling of the GABA agonist thiomuscimol

Journal of Labelled Compounds and Radiopharmaceuticals, 1984

... 1. 2 . 3 . 4 . 5 . 6 . 7. 8 . 9 . 10. 11. 1 2 * REFERENCES Roberts, E., Chase, TN and Tower, ... more ... 1. 2 . 3 . 4 . 5 . 6 . 7. 8 . 9 . 10. 11. 1 2 * REFERENCES Roberts, E., Chase, TN and Tower, DB Eds., GABA in Nervous System Function, Raven Press, New York 1976 Krogsgaard-Larsen, P., Scheel-Kruger, J. and Kofod, H. Eds., GABA-Neurotransmitters. Pharmacochemical, Bio-...

Research paper thumbnail of (−)-( R )-5,5-Dimethylmorpholinyl-2-acetic Acid Ethyl Ester Hydrochloride, C 10 H 20 NO 3 + .Cl −

Acta Crystallographica Section C Crystal Structure Communications, 1997

Research paper thumbnail of Organic Hydroxylamine Derivatives. IX. Structural Analogues of GABA of the Isoxazole Enol-betaine Type. Improved Synthesis and the Crystal Structure of 3-Hydroxy-5-(2-aminoethyl)isoxazole Zwitterion (Homomuscimol)

Acta Chemica Scandinavica, 1974