Abstract:
:This article describes the expected phenotypic behavior of all types of ligands in constitutively active receptor systems and, in particular, the molecular mechanisms of inverse agonism. The possible physiological relevance of inverse agonism also is discussed. Competitive antagonists with the molecular property of negative efficacy demonstrate inverse agonism in constitutively active receptor systems. This is a phenotypic behavior that can only be observed in the appropriate assay; a lack of observed inverse agonism is evidence that the ligand does not possess negative efficacy only if it can be shown that constitutive receptor activity is present. In the absence of constitutive activity, inverse agonists behave as simple competitive antagonists. A survey of 105 articles on the activity of 380 antagonists on 73 biological G-protein-coupled receptor targets indicates that, in this sample dataset, 322 are inverse agonists and 58 (15%) are neutral antagonists. The predominance of inverse agonism agrees with theoretical predictions which indicate that neutral antagonists are the minority species in pharmacological space.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Kenakin Tdoi
10.1124/mol.65.1.2keywords:
subject
Has Abstractpub_date
2004-01-01 00:00:00pages
2-11issue
1eissn
0026-895Xissn
1521-0111pii
65/1/2journal_volume
65pub_type
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