Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

Niklas Sköld; Birgitte Nielsen; Jakob Olsen; Liwei Han; Lars Olsen; Ulf Madsen; Jesper Langgaard Kristensen; Darryl S Pickering; Tommy N Johansen

doi:10.1016/j.bmc.2014.07.045

Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

Niklas Sköld, Birgitte Nielsen, Jakob Olsen, Liwei Han, Lars Olsen, Ulf Madsen, Jesper Langgaard Kristensen, Darryl S Pickering, Tommy N Johansen

4 Citationer (Scopus)

Abstract

In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.

Originalsprog	Engelsk
Tidsskrift	Bioorganic & Medicinal Chemistry
Vol/bind	22
Udgave nummer	19
Sider (fra-til)	5368-5377
Antal sider	10
ISSN	0968-0896
DOI	https://doi.org/10.1016/j.bmc.2014.07.045
Status	Udgivet - 1 okt. 2014

Adgang til dokumentet

10.1016/j.bmc.2014.07.045

Fingeraftryk

Dyk ned i forskningsemnerne om 'Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites'. Sammen danner de et unikt fingeraftryk.

Citationsformater

Sköld, N., Nielsen, B., Olsen, J., Han, L., Olsen, L., Madsen, U., Kristensen, J. L., Pickering, D. S., & Johansen, T. N. (2014). Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites. Bioorganic & Medicinal Chemistry, 22(19), 5368-5377. https://doi.org/10.1016/j.bmc.2014.07.045

Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites. / Sköld, Niklas; Nielsen, Birgitte; Olsen, Jakob et al.
I: Bioorganic & Medicinal Chemistry, Bind 22, Nr. 19, 01.10.2014, s. 5368-5377.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Sköld, N, Nielsen, B, Olsen, J, Han, L, Olsen, L, Madsen, U , Kristensen, JL , Pickering, DS & Johansen, TN 2014, 'Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites', Bioorganic & Medicinal Chemistry, bind 22, nr. 19, s. 5368-5377. https://doi.org/10.1016/j.bmc.2014.07.045

Sköld N, Nielsen B, Olsen J, Han L, Olsen L, Madsen U et al. Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites. Bioorganic & Medicinal Chemistry. 2014 okt. 1;22(19):5368-5377. doi: 10.1016/j.bmc.2014.07.045

Sköld, Niklas ; Nielsen, Birgitte ; Olsen, Jakob et al. / Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites. I: Bioorganic & Medicinal Chemistry. 2014 ; Bind 22, Nr. 19. s. 5368-5377.

@article{57ffa1ebbaad4474b605b0b72d6ceb5d,

title = "Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites",

abstract = "In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.",

author = "Niklas Sk{\"o}ld and Birgitte Nielsen and Jakob Olsen and Liwei Han and Lars Olsen and Ulf Madsen and Kristensen, {Jesper Langgaard} and Pickering, {Darryl S} and Johansen, {Tommy N}",

note = "Copyright {\textcopyright} 2014. Published by Elsevier Ltd.",

year = "2014",

month = oct,

day = "1",

doi = "10.1016/j.bmc.2014.07.045",

language = "English",

volume = "22",

pages = "5368--5377",

journal = "Bioorganic & Medicinal Chemistry",

issn = "0968-0896",

publisher = "Pergamon Press",

number = "19",

}

TY - JOUR

T1 - Design, synthesis and in vitro pharmacology of GluK1 and GluK3 antagonists. Studies towards the design of subtype-selective antagonists through 2-carboxyethyl-phenylalanines with substituents interacting with non-conserved residues in the GluK binding sites

AU - Sköld, Niklas

AU - Nielsen, Birgitte

AU - Olsen, Jakob

AU - Han, Liwei

AU - Olsen, Lars

AU - Madsen, Ulf

AU - Kristensen, Jesper Langgaard

AU - Pickering, Darryl S

AU - Johansen, Tommy N

PY - 2014/10/1

Y1 - 2014/10/1

N2 - In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.

AB - In order to identify compounds selective for the GluK1 and GluK3 subtypes of kainate receptors we have designed and synthesized a series of (S)-2-amino-3-((2-carboxyethyl)phenyl)propanoic acid analogs with hydrogen bond donating and accepting substituents on the aromatic ring. Based on crystal structures of GluK1 in complex with related ligands, the compounds were designed to explore possible interactions with non-conserved residues outside the glutamate ligand binding site and challenge the water binding network. Apart from obtaining GluK1 selective antagonists one analog with a phenyl-substituted urea (compound 31) showed some preference for GluK3 over GluK1-receptors. Docking studies indicate that this preference may be attributed to contacts between the NH of the urea substituent and non-conserved Ser741 and Ser761 residues.

U2 - 10.1016/j.bmc.2014.07.045

DO - 10.1016/j.bmc.2014.07.045

M3 - Journal article

C2 - 25172149

SN - 0968-0896

VL - 22

SP - 5368

EP - 5377

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 19

ER -