Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

Rasmus P Clausen; Hans Bräuner-Osborne; Jeremy R Greenwood; Mette B Hermit; Tine B Stensbøl; Birgitte Nielsen; Povl Krogsgaard-Larsen

Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

Rasmus P Clausen, Hans Bräuner-Osborne, Jeremy R Greenwood, Mette B Hermit, Tine B Stensbøl, Birgitte Nielsen, Povl Krogsgaard-Larsen

15 Citations (Scopus)

Abstract

Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized by conformational analysis, comparison with the potent and specific group II mGluR agonist (-)-LY379268 [(-)-12], and docking to a homology model of mGluR2.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	45
Issue number	19
Pages (from-to)	4240-5
ISSN	0022-2623
Publication status	Published - 12 Sept 2002

Keywords

Amino Acids
Animals
Bicyclo Compounds, Heterocyclic
Binding Sites
Cerebral Cortex
Models, Molecular
Radioligand Assay
Rats
Receptors, Metabotropic Glutamate
Stereoisomerism
Structure-Activity Relationship
Thiadiazoles

Cite this

Clausen, R. P., Bräuner-Osborne, H., Greenwood, J. R., Hermit, M. B., Stensbøl, T. B., Nielsen, B., & Krogsgaard-Larsen, P. (2002). Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid. Journal of Medicinal Chemistry, 45(19), 4240-5.

Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid. / Clausen, Rasmus P ; Bräuner-Osborne, Hans; Greenwood, Jeremy R et al.

In: Journal of Medicinal Chemistry, Vol. 45, No. 19, 12.09.2002, p. 4240-5.

Research output: Contribution to journal › Journal article › Research › peer-review

Clausen, RP , Bräuner-Osborne, H, Greenwood, JR, Hermit, MB, Stensbøl, TB, Nielsen, B & Krogsgaard-Larsen, P 2002, 'Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid', Journal of Medicinal Chemistry, vol. 45, no. 19, pp. 4240-5.

@article{f9854a1163034f70a87af6c23dbe2f84,

title = "Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid",

abstract = "Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized by conformational analysis, comparison with the potent and specific group II mGluR agonist (-)-LY379268 [(-)-12], and docking to a homology model of mGluR2.",

keywords = "Amino Acids, Animals, Bicyclo Compounds, Heterocyclic, Binding Sites, Cerebral Cortex, Models, Molecular, Radioligand Assay, Rats, Receptors, Metabotropic Glutamate, Stereoisomerism, Structure-Activity Relationship, Thiadiazoles",

author = "Clausen, {Rasmus P} and Hans Br{\"a}uner-Osborne and Greenwood, {Jeremy R} and Hermit, {Mette B} and Stensb{\o}l, {Tine B} and Birgitte Nielsen and Povl Krogsgaard-Larsen",

year = "2002",

month = sep,

day = "12",

language = "English",

volume = "45",

pages = "4240--5",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "19",

}

TY - JOUR

T1 - Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

AU - Clausen, Rasmus P

AU - Bräuner-Osborne, Hans

AU - Greenwood, Jeremy R

AU - Hermit, Mette B

AU - Stensbøl, Tine B

AU - Nielsen, Birgitte

AU - Krogsgaard-Larsen, Povl

PY - 2002/9/12

Y1 - 2002/9/12

N2 - Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized by conformational analysis, comparison with the potent and specific group II mGluR agonist (-)-LY379268 [(-)-12], and docking to a homology model of mGluR2.

AB - Homologation of analogues of the central excitatory neurotransmitter glutamic acid (Glu), in which the distal carboxy group has been bioisosterically replaced by acidic heterocyclic units, has previously provided subtype selective ligands for metabotropic Glu receptors (mGluRs). The (S)-form of the 1,2,5-thiadiazol-3-ol Glu analogue, 2-amino-3-(4-hydroxy[1,2,5]thiadiazol-3-yl)propionic acid (TDPA, 6), is an 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, which in addition stereospecifically activates group I mGluRs. We have now synthesized the (S)- and (R)-forms of 2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid (homo-TDPA, 7) and shown that whereas neither enantiomer interacts with AMPA receptors, (S)- and (R)-7 appear to be selective and equipotent agonists at group II mGluRs as represented by the mGluR2 subtype. The activities of (S)- and (R)-7 are rationalized by conformational analysis, comparison with the potent and specific group II mGluR agonist (-)-LY379268 [(-)-12], and docking to a homology model of mGluR2.

KW - Amino Acids

KW - Animals

KW - Bicyclo Compounds, Heterocyclic

KW - Binding Sites

KW - Cerebral Cortex

KW - Models, Molecular

KW - Radioligand Assay

KW - Rats

KW - Receptors, Metabotropic Glutamate

KW - Stereoisomerism

KW - Structure-Activity Relationship

KW - Thiadiazoles

M3 - Journal article

C2 - 12213064

SN - 0022-2623

VL - 45

SP - 4240

EP - 4245

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 19

ER -

Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S)- and (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)butyric acid

Abstract

Keywords

Fingerprint

Cite this