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Research ArticleOriginal Article

The CCR5 Receptor-Based Mechanism of Action of 873140, a Potent Allosteric Noncompetitive HIV Entry Inhibitor

Christian Watson, Stephen Jenkinson, Wieslaw Kazmierski and Terry Kenakin
Molecular Pharmacology April 2005, 67 (4) 1268-1282; DOI: https://doi.org/10.1124/mol.104.008565
Christian Watson
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Stephen Jenkinson
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Wieslaw Kazmierski
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Terry Kenakin
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Abstract

4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pKB = 8.6 ± 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1′-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidin-4-yl}methanone O-ethyloxime (Sch-C; SCH 351125), 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R)-2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinyl]carbonyl}pyrimidine (Sch-D; SCH 417,690), 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenyl-propyl)cyclohexanecarboxamide (UK-427,857), and N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK779) blocked the binding of both chemokines 125I-MIP-1α (also known as 125I-CCL3, 125I-LD78) and 125I-RANTES (125I-CCL5), 873140 was an ineffectual antagonist of 125I-RANTES (regulated on activation normal T cell expressed and secreted) binding (but did block binding of 125I-MIP-1α). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 (RANTES) (as did the other antagonists), indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe-dependent, consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of <0.004 h- 1 (t1/2 > 136 h). Coadministration studies of 873140 with the four other allosteric antagonists yielded data that are consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. Although these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor, as indicated by their differential effects on the binding of 125I-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.

  • Received October 21, 2004.
  • Accepted January 10, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 67 (4)
Molecular Pharmacology
Vol. 67, Issue 4
1 Apr 2005
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Research ArticleOriginal Article

The CCR5 Receptor-Based Mechanism of Action of 873140, a Potent Allosteric Noncompetitive HIV Entry Inhibitor

Christian Watson, Stephen Jenkinson, Wieslaw Kazmierski and Terry Kenakin
Molecular Pharmacology April 1, 2005, 67 (4) 1268-1282; DOI: https://doi.org/10.1124/mol.104.008565

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Research ArticleOriginal Article

The CCR5 Receptor-Based Mechanism of Action of 873140, a Potent Allosteric Noncompetitive HIV Entry Inhibitor

Christian Watson, Stephen Jenkinson, Wieslaw Kazmierski and Terry Kenakin
Molecular Pharmacology April 1, 2005, 67 (4) 1268-1282; DOI: https://doi.org/10.1124/mol.104.008565
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