Analogues of 3-hydroxyisoxazole-containing Glutamate Receptor Ligands Based on the 3-hydroxypyrazole-moiety: Design, Synthesis and Pharmacological Characterization

Overview

Journal Neurochem Res

Specialties Chemistry
Neurology

Date 2014 May 23

PMID 24848194

Authors

Lars Jorgensen

Birgitte Nielsen

Darryl S Pickering

Anders S Kristensen

Karla Frydenvang

Ulf Madsen

Rasmus P Clausen

Affiliations

Soon will be listed here.

Abstract

A series of analogues of the glutamate receptor ligands (S)-2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propionic acid (AMPA) and AMOA were synthesized in which the 3-hydroxyisoxazole moiety was exchanged for a 3-hydroxypyrazole moiety. This exchange enables further substitution at the additional nitrogen atom in the heterocyclic core. Several of the analogues have activity at AMPA receptors equipotent to the antagonist ATPO, demonstrating that additional substitution can be accommodated in the antagonist binding site. Modelling studies offer an explanation for the pharmacological pattern observed for the compounds and suggest that this scaffold may be developed further to obtain subtype selective antagonists.

References

Hald H, Naur P, Pickering D, Sprogoe D, Madsen U, Timmermann D . Partial agonism and antagonism of the ionotropic glutamate receptor iGLuR5: structures of the ligand-binding core in complex with domoic acid and 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid. J Biol Chem. 2007; 282(35):25726-36. DOI: 10.1074/jbc.M700137200. View

Sagot E, Pickering D, Pu X, Umberti M, Stensbol T, Nielsen B . Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotropic glutamate receptor subtypes 5, 6, and 7. J Med Chem. 2008; 51(14):4093-103. DOI: 10.1021/jm800092x. View

Ransom R, Stec N . Cooperative modulation of [3H]MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine, and polyamines. J Neurochem. 1988; 51(3):830-6. DOI: 10.1111/j.1471-4159.1988.tb01818.x. View

Hansen K, Yuan H, Traynelis S . Structural aspects of AMPA receptor activation, desensitization and deactivation. Curr Opin Neurobiol. 2007; 17(3):281-8. DOI: 10.1016/j.conb.2007.03.014. View

Wahl P, Anker C, Traynelis S, Egebjerg J, Rasmussen J, Krogsgaard-Larsen P . Antagonist properties of a phosphono isoxazole amino acid at glutamate R1-4 (R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid receptor subtypes. Mol Pharmacol. 1998; 53(3):590-6. DOI: 10.1124/mol.53.3.590. View

Brauner-Osborne H, Egebjerg J, Nielsen E, Madsen U, Krogsgaard-Larsen P . Ligands for glutamate receptors: design and therapeutic prospects. J Med Chem. 2000; 43(14):2609-45. DOI: 10.1021/jm000007r. View

Poulsen M, Lucas S, Stromgaard K, Kristensen A . Evaluation of PhTX-74 as subtype-selective inhibitor of GluA2-containing AMPA receptors. Mol Pharmacol. 2013; 85(2):261-8. DOI: 10.1124/mol.113.089961. View

Madsen U, Bang-Andersen B, BREHM L, Christensen I, Ebert B, Kristoffersen I . Synthesis and pharmacology of highly selective carboxy and phosphono isoxazole amino acid AMPA receptor antagonists. J Med Chem. 1996; 39(8):1682-91. DOI: 10.1021/jm950826p. View

Moller E, Egebjerg J, BREHM L, Stensbol T, Johansen T, Madsen U . Resolution, absolute stereochemistry, and enantiopharmacology of the GluR1-4 and GluR5 antagonist 2-amino-3-[5-tert-butyl-3-(phosphonomethoxy)-4-isoxazolyl]propionic acid. Chirality. 1999; 11(10):752-9. DOI: 10.1002/(SICI)1520-636X(1999)11:10<752::AID-CHIR3>3.0.CO;2-T. View

10.

Vogensen S, Greenwood J, Varming A, Brehm L, Pickering D, Nielsen B . A stereochemical anomaly: the cyclised (R)-AMPA analogue (R)-3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-5-carboxylic acid [(R)-5-HPCA] resembles (S)-AMPA at glutamate receptors. Org Biomol Chem. 2004; 2(2):206-13. DOI: 10.1039/b310450h. View

11.

Traynelis S, Wollmuth L, McBain C, Menniti F, Vance K, Ogden K . Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010; 62(3):405-96. PMC: 2964903. DOI: 10.1124/pr.109.002451. View

12.

Hermit M, Greenwood J, Nielsen B, Bunch L, Jorgensen C, Vestergaard H . Ibotenic acid and thioibotenic acid: a remarkable difference in activity at group III metabotropic glutamate receptors. Eur J Pharmacol. 2004; 486(3):241-50. DOI: 10.1016/j.ejphar.2003.12.033. View

13.

Assaf Z, Larsen A, Venskutonyte R, Han L, Abrahamsen B, Nielsen B . Chemoenzymatic synthesis of new 2,4-syn-functionalized (S)-glutamate analogues and structure-activity relationship studies at ionotropic glutamate receptors and excitatory amino acid transporters. J Med Chem. 2013; 56(4):1614-28. DOI: 10.1021/jm301433m. View

14.

Sills M, FAGG G, Pozza M, Angst C, Brundish D, Hurt S . [3H]CGP 39653: a new N-methyl-D-aspartate antagonist radioligand with low nanomolar affinity in rat brain. Eur J Pharmacol. 1991; 192(1):19-24. DOI: 10.1016/0014-2999(91)90063-v. View

15.

Javitt D . Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry. 2004; 9(11):984-97, 979. DOI: 10.1038/sj.mp.4001551. View

16.

Honore T, Nielsen M . Complex structure of quisqualate-sensitive glutamate receptors in rat cortex. Neurosci Lett. 1985; 54(1):27-32. DOI: 10.1016/s0304-3940(85)80113-0. View

17.

Braitman D, Coyle J . Inhibition of [3H]kainic acid receptor binding by divalent cations correlates with ion affinity for the calcium channel. Neuropharmacology. 1987; 26(9):1247-51. DOI: 10.1016/0028-3908(87)90083-9. View

18.

Krogsgaard-Larsen P, Honore T, Hansen J, Curtis D, Lodge D . New class of glutamate agonist structurally related to ibotenic acid. Nature. 1980; 284(5751):64-6. DOI: 10.1038/284064a0. View

19.

Hogner A, Greenwood J, Liljefors T, Lunn M, Egebjerg J, Larsen I . Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX. J Med Chem. 2003; 46(2):214-21. DOI: 10.1021/jm020989v. View

20.

Sobolevsky A, Rosconi M, Gouaux E . X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 2009; 462(7274):745-56. PMC: 2861655. DOI: 10.1038/nature08624. View