Driving Changes in Ligand Theory

AGONIZING DIFFERENCES:© 2004 Macmillan Magazines Ltd.(A) GPCR agonists increase the proportion of active receptor states; inverse agonists decrease the proportion of active receptor states; and antagonists inhibit the action of other ligands. (B) In systems with low constitutive receptor activity, inverse agonists will seem to have minimal effect, but might have more effect in a system with high activity. (from Nat Rev Drug Disc, 3:577–626, 2004.)Pharmacologists traditionally divide l

Written byMark Greener

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(A) GPCR agonists increase the proportion of active receptor states; inverse agonists decrease the proportion of active receptor states; and antagonists inhibit the action of other ligands. (B) In systems with low constitutive receptor activity, inverse agonists will seem to have minimal effect, but might have more effect in a system with high activity. (from Nat Rev Drug Disc, 3:577–626, 2004.)

Pharmacologists traditionally divide ligands into agonists, which stimulate receptors, and antagonists, which bind to receptors and block endogenous mediators. According to the conventional view, the agonist fits into the receptor, like a key fits a car's ignition, switching on the internal machinery. Antagonists fit the ignition, but block endogenous transmitters.

But recent studies suggest that many receptors spontaneously activate internal machinery. In these cases, the receptor is more akin to an accelerator. Agonists increase the receptor's spontaneous activity, revving the engine. A more recently ...

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