New insights in insurmountable antagonism

Abstract

Antagonists that produce parallel rightward shifts of agonist dose-response curves with no alteration of the maximal response are traditionally classified as surmountable, while insurmountable antagonists also depress the maximal response. Although the longevity of the antagonist-receptor complex is quoted in many studies to explain insurmountable antagonism, slowly interconverting receptor conformations, allosteric binding sites, and receptor internalization have been evoked as alternative explanations. To complicate matters even further, insurmountable antagonism is not only drug-related; it may also depend on the tissue, species and experimental design. For the sake of drug development, it is important to elucidate the molecular mechanisms of insurmountable antagonism. New experimental approaches, such as intact cell studies and the use of computer-assisted simulations based on dynamic receptor models, herald the advent of better insight in the future.

Pharmacological Profile of JNJ-27141491 [(S)-3-[3,4-Difluorophenyl)-propyl]-5-isoxazol-5-yl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxyl Acid Methyl Ester], as a Noncompetitive and Orally Active Antagonist of the Human Chemokine Receptor CCR2

“…Both compounds inhibit chemokine receptor function, with low effect on binding (Sabroe et al, 2000;Bertini et al, 2004). Our results showing that JNJ-27141491 behaves as a reversible inhibitor of hCCR2 and as an insurmountable antagonist of hCCR2 in Schild analyses in both pre-and coincubation settings (Vauquelin et al, 2002) suggest that JNJ-27141491 is a noncompetitive CCR2 antagonist. Insurmountable antagonists exhibiting adequate receptor selectivity may have great potential as therapeutic drugs, because they exert their blocking action irrespective of the concentration of the natural agonist.…”

“…To find out whether an insurmountable antagonist is competitive, it is essential for the receptors to be exposed to the antagonist and agonist simultaneously. A decrease of the maximal agonist-evoked response is only to be expected in noncompetitive antagonism (Vauquelin et al, 2002). As shown in Fig.…”

Phage display and hybridoma generation of antibodies to human CXCR2 yields antibodies with distinct mechanisms and epitopes

“…HY29-1 showed insurmountable antagonism, which can be the result of allosteric or orthosteric blockade depending on the kinetics of the interaction of agonist and antagonist with the receptor. 59,60 In these assays the antibody was pre-equilibrated with the receptor and then agonist added to stimulate the functional response. Under these conditions the HY29-1 antagonism did not appear to reach a maximal dextral displacement and was similar for both IL-8 and Gro-a agonists (probe independent), suggesting potential interaction of the antibody at an orthosteric site.…”

Myracrondruon urundeuva Allemo: Chemical composition, antioxidant activity, antimicrobial activity and inotropic effect

“…Figure 5B showed that there was a displacement of almost twice the EC50 for the positive inotropic effect, going from 3250 ± 727 μg/ml in the control CaCl 2 only, to 6240 ± 854 μg/mL for CaCl 2 treatment and the extract, characterized the mechanism as calcium channel antagonism. Because the maximum effect not be maintained with the extract of the increase, it was revealed that this antagonism is not competitive, meaning that the extract acts in a different location agonist (CaCl 2 ) (Vauquelin et al, 2002).…”