Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship? (original) (raw)
OtherMINIREVIEW
Molecular Pharmacology December 2007, 72 (6) 1393-1401; DOI: https://doi.org/10.1124/mol.107.040352
Abstract
This article describes functional selectivity of agonists and antagonists and distinguishes conventional cell-based functional selectivity, where the strength of signal produces selective signaling in various organs, from true receptor active-state based selectivity, also alternatively referred to in the literature as “stimulus trafficking,” “biased agonism,” and “collateral efficacy.” This latter mechanism of selectivity depends on the ligand-related conformation of the receptor and is not compatible with the parsimonious view that agonists produce a single receptor active state. In addition, protean agonism is described, whereby a ligand produces positive agonism in quiescent systems and inverse agonism in constitutively active systems. This is a special case of active state-based selectivity in which the ligand produces an active state that is of lower efficacy than the natural constitutively active state. It is postulated that receptor active-state based selectivity, unlike cell-based functional selectivity, is controllable through the chemical structure of the ligand and is therefore more likely to be a viable avenue for therapeutic selectivity in the clinic. Reasons are given for differentiating receptor active-state based selectivity from conventional functional organ selectivity.
Footnotes
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.107.040352.
ABBREVIATIONS: HEK, human embryonic kidney; PACAP, pituitary adenylyl cyclase-activating protein; GRK, G protein-coupled receptor kinase; CCR5, chemokine receptor; ICI118,551, (±)-1-[2,3-(dihydro-7-methyl-1_H_-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; RANTES, regulated on activation normal T cell expressed and secreted; PDZ, postsynaptic density 95/disc-large/zona occludens; ICI174,864, 2[N,N′-diallyl-Tyr1,Aib2,3]Leu5-enkephalin; LP1805, N,N-(2-methylnaphthyl-benzyl)-2-aminoacetonitrile; AMD3100, 1,1′-[1,4-phenylenebis(methylene)]bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride; UK-14304, 5-bromo-_N_-(4,5-dihydro-1_H_-imidazol-2-yl)-6-quinoxalinamine.
- Received July 29, 2007.
- Accepted September 27, 2007.
The American Society for Pharmacology and Experimental Therapeutics
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