New insights in insurmountable antagonism

• Published in: Fundamental & clinical pharmacology Vol. 16; no. 4; pp. 263 - 272
• Main Authors: Vauquelin, G., Van Liefde, I., Birzbier, B. B., Vanderheyden, P. M. L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science, Ltd 01.08.2002
• Subjects: Allosteric Regulation; antagonism; Binding, Competitive; cell lines; Computer Simulation; Humans; insurmountable/surmountable; Models, Biological; noncompetitive/competitive; receptor; Receptors, Cell Surface - agonists; Receptors, Cell Surface - antagonists & inhibitors; Receptors, Cell Surface - metabolism
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1046/j.1472-8206.2002.00095.x

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.