Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors

Dennis Verzijl, Stefania Storelli, Danny J. Scholten, Leontien Bosch, Todd A. Reinhart, Daniel Streblow, Cornelis P. Tensen, Carlos P. Fitzsimons, Guido J R Zaman, James E. Pease, Iwan J P De Esch, Martine J. Smit, Rob Leurs

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10, and CXCL11 are expressed at sites of inflammation, and they attract CXCR3-bearing lymphocytes, thus contributing to the inflammatory process. In this study, we characterize five nonpeptidergic compounds of different chemical classes that block the action of CXCL10 and CXCL11 at the human CXCR3, i.e., the 3H-pyrido[2,3-d]pyrimidin-4-one derivatives N-1R-[3-(4-ethoxy-phenyl)-4-oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3-ylmethyl-2-(4-fluoro-3- trifluoromethylphenyl)-acetamide (VUF10472/NBI-74330) and N-1R-[3-(4-ethoxy- phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3- ylmethyl-2-(4-trifluoromethoxy-phenyl)-acetamide (VUF10085/AMG-487), the 3H-quinazolin-4-one decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-ethyl}-(2-dimethylamino-ethyl)-amide (VUF5834), the imidazolium compound 1,3-bis-[2-(3,4-dichloro-phenyl)-2-oxo-ethyl]-3H-imidazol-1-ium bromide (VUF10132), and the quaternary ammonium anilide N,N-dimethyl-N-[4-[[[2- (4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]-carbonyl]amino]benzyl] tetrahydro-2H-pyran-4-aminium chloride (TAK-779). To understand the action of these CXCR3 antagonists in various animal models of disease, the compounds were also tested at rat and mouse CXCR3, as well as at CXCR3 from rhesus macaque, which was cloned and characterized for the first time in this study. Except for TAK-779, all compounds show slightly lower affinity for rodent CXCR3 than for primate CXCR3. In addition, we have characterized the molecular mechanism of action of the various antagonists at the human CXCR3 receptor. All tested compounds act as noncompetitive antagonists at CXCR3. Moreover, this noncompetitive behavior is accompanied by inverse agonistic properties of all five compounds as determined on an identified constitutively active mutant of CXCR3, CXCR3 N3.35A. It is interesting to note that all compounds except TAK-779 act as full inverse agonists at CXCR3 N3.35A. TAK-779 shows weak partial inverse agonism at CXCR3 N3.35A, and it probably has a different mode of interaction with CXCR3 than the other two classes of small-molecule inverse agonists.

Original languageEnglish (US)
Pages (from-to)544-555
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume325
Issue number2
DOIs
StatePublished - May 2008

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CXCR3 Receptors
Chemokine Receptors
Primates
Rodentia
Anilides
Animal Disease Models
Graft Rejection
Macaca mulatta
Bromides
Ammonium Compounds
Psoriasis
Amides
Multiple Sclerosis
Allografts
Rheumatoid Arthritis
TAK 779
Lymphocytes
Ligands
Inflammation

ASJC Scopus subject areas

  • Pharmacology
  • Medicine(all)

Cite this

Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. / Verzijl, Dennis; Storelli, Stefania; Scholten, Danny J.; Bosch, Leontien; Reinhart, Todd A.; Streblow, Daniel; Tensen, Cornelis P.; Fitzsimons, Carlos P.; Zaman, Guido J R; Pease, James E.; De Esch, Iwan J P; Smit, Martine J.; Leurs, Rob.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 325, No. 2, 05.2008, p. 544-555.

Research output: Contribution to journalArticle

Verzijl, D, Storelli, S, Scholten, DJ, Bosch, L, Reinhart, TA, Streblow, D, Tensen, CP, Fitzsimons, CP, Zaman, GJR, Pease, JE, De Esch, IJP, Smit, MJ & Leurs, R 2008, 'Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors', Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 2, pp. 544-555. https://doi.org/10.1124/jpet.107.134783
Verzijl, Dennis ; Storelli, Stefania ; Scholten, Danny J. ; Bosch, Leontien ; Reinhart, Todd A. ; Streblow, Daniel ; Tensen, Cornelis P. ; Fitzsimons, Carlos P. ; Zaman, Guido J R ; Pease, James E. ; De Esch, Iwan J P ; Smit, Martine J. ; Leurs, Rob. / Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 325, No. 2. pp. 544-555.
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T1 - Noncompetitive antagonism and inverse agonism as mechanism of action of nonpeptidergic antagonists at primate and rodent CXCR3 chemokine receptors

AU - Verzijl, Dennis

AU - Storelli, Stefania

AU - Scholten, Danny J.

AU - Bosch, Leontien

AU - Reinhart, Todd A.

AU - Streblow, Daniel

AU - Tensen, Cornelis P.

AU - Fitzsimons, Carlos P.

AU - Zaman, Guido J R

AU - Pease, James E.

AU - De Esch, Iwan J P

AU - Smit, Martine J.

AU - Leurs, Rob

PY - 2008/5

Y1 - 2008/5

N2 - The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10, and CXCL11 are expressed at sites of inflammation, and they attract CXCR3-bearing lymphocytes, thus contributing to the inflammatory process. In this study, we characterize five nonpeptidergic compounds of different chemical classes that block the action of CXCL10 and CXCL11 at the human CXCR3, i.e., the 3H-pyrido[2,3-d]pyrimidin-4-one derivatives N-1R-[3-(4-ethoxy-phenyl)-4-oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3-ylmethyl-2-(4-fluoro-3- trifluoromethylphenyl)-acetamide (VUF10472/NBI-74330) and N-1R-[3-(4-ethoxy- phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3- ylmethyl-2-(4-trifluoromethoxy-phenyl)-acetamide (VUF10085/AMG-487), the 3H-quinazolin-4-one decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-ethyl}-(2-dimethylamino-ethyl)-amide (VUF5834), the imidazolium compound 1,3-bis-[2-(3,4-dichloro-phenyl)-2-oxo-ethyl]-3H-imidazol-1-ium bromide (VUF10132), and the quaternary ammonium anilide N,N-dimethyl-N-[4-[[[2- (4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]-carbonyl]amino]benzyl] tetrahydro-2H-pyran-4-aminium chloride (TAK-779). To understand the action of these CXCR3 antagonists in various animal models of disease, the compounds were also tested at rat and mouse CXCR3, as well as at CXCR3 from rhesus macaque, which was cloned and characterized for the first time in this study. Except for TAK-779, all compounds show slightly lower affinity for rodent CXCR3 than for primate CXCR3. In addition, we have characterized the molecular mechanism of action of the various antagonists at the human CXCR3 receptor. All tested compounds act as noncompetitive antagonists at CXCR3. Moreover, this noncompetitive behavior is accompanied by inverse agonistic properties of all five compounds as determined on an identified constitutively active mutant of CXCR3, CXCR3 N3.35A. It is interesting to note that all compounds except TAK-779 act as full inverse agonists at CXCR3 N3.35A. TAK-779 shows weak partial inverse agonism at CXCR3 N3.35A, and it probably has a different mode of interaction with CXCR3 than the other two classes of small-molecule inverse agonists.

AB - The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10, and CXCL11 are expressed at sites of inflammation, and they attract CXCR3-bearing lymphocytes, thus contributing to the inflammatory process. In this study, we characterize five nonpeptidergic compounds of different chemical classes that block the action of CXCL10 and CXCL11 at the human CXCR3, i.e., the 3H-pyrido[2,3-d]pyrimidin-4-one derivatives N-1R-[3-(4-ethoxy-phenyl)-4-oxo-3,4- dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3-ylmethyl-2-(4-fluoro-3- trifluoromethylphenyl)-acetamide (VUF10472/NBI-74330) and N-1R-[3-(4-ethoxy- phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl-N-pyridin-3- ylmethyl-2-(4-trifluoromethoxy-phenyl)-acetamide (VUF10085/AMG-487), the 3H-quinazolin-4-one decanoic acid {1-[3-(4-cyano-phenyl)-4-oxo-3,4-dihydro- quinazolin-2-yl]-ethyl}-(2-dimethylamino-ethyl)-amide (VUF5834), the imidazolium compound 1,3-bis-[2-(3,4-dichloro-phenyl)-2-oxo-ethyl]-3H-imidazol-1-ium bromide (VUF10132), and the quaternary ammonium anilide N,N-dimethyl-N-[4-[[[2- (4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]-carbonyl]amino]benzyl] tetrahydro-2H-pyran-4-aminium chloride (TAK-779). To understand the action of these CXCR3 antagonists in various animal models of disease, the compounds were also tested at rat and mouse CXCR3, as well as at CXCR3 from rhesus macaque, which was cloned and characterized for the first time in this study. Except for TAK-779, all compounds show slightly lower affinity for rodent CXCR3 than for primate CXCR3. In addition, we have characterized the molecular mechanism of action of the various antagonists at the human CXCR3 receptor. All tested compounds act as noncompetitive antagonists at CXCR3. Moreover, this noncompetitive behavior is accompanied by inverse agonistic properties of all five compounds as determined on an identified constitutively active mutant of CXCR3, CXCR3 N3.35A. It is interesting to note that all compounds except TAK-779 act as full inverse agonists at CXCR3 N3.35A. TAK-779 shows weak partial inverse agonism at CXCR3 N3.35A, and it probably has a different mode of interaction with CXCR3 than the other two classes of small-molecule inverse agonists.

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