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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....


Many G-protein-coupled receptors (GPCRs) exist in active and inactive conformations, and may spontaneously switch between the different forms.1 Agonists promote a change from inactive to active forms. Inverse agonists selectively enrich a less active conformation. But in tissues with low levels of activity, inverse agonists can act as antagonists, blocking the endogenous transmitter. Indeed, some 85% of drugs traditionally regarded as antagonists seem to be inverse agonists.2 Protean agonists extend this concept, acting as either inverse agonists or agonists depending on the GPCR's constitutive activity, either promoting a switch to a less active conformation or enriching the active.1

While the concept is proving valuable for pharmacologists, the idea could have even wider implications for other fields of bioscience. For example, a growing body of evidence links agouti protein (a paracrine factor that regulates mammalian skin color) with obesity, type II diabetes, and some forms of cancer. "Agouti-related protein is an endogenous inverse agonist at melanocortin receptors in the brain, suppressing their constitutive activation and participating in control of body weight," comments Philip Strange at the University of Reading, UK.

"We were intrigued by the observation that serotonin could behave as a protean agonist at two receptor subtypes (5-HT1A and 5-HT1B) when expressed in cultured cells," says Didier Cussac from the French pharmaceutical company, Pierre Fabre Laboratories. The switch from agonist to inverse agonist emerged as a function of sodium chloride concentration. "Given that NaCl is a fundamental regulator of neuronal polarization, this raises the intriguing possibility that endogenous agonists may exert opposite influences depending on neuronal activation state."

Pierre Fabre is investigating whether inverse agonists may yield a new generation of psychiatric drugs. Serotonin 5-HT1B and 5-HT1D receptors, inhibitory autoreceptors that regulate serotonin release, exhibit considerable constitutive in vitro activity. "Inverse agonists at 5-HT1B and 5-HT1D receptors might, therefore, be supposed to reduce the inhibitory influence on serotonin release and alleviate the impaired serotonergic transmission associated with depressive states," says Adrian Newman-Tancredi, also at Pierre Fabre.

Initial studies failed to distinguish a 5-HT1B inverse agonist from an antagonist, says Newman-Tancredi. Other evidence suggests, however, that 5-HT1B inverse agonists could treat memory dysfunction, while 5-HT2C receptors might constitutively control brain dopamine release.

Meanwhile, a group led by Paul Prather at the University of Arkansas, Little Rock, demonstrated that exposing cells to opioids for extended periods converted antagonists into inverse agonists. Such adaptations could contribute to physical dependence following chronic opioid use. "Once the mechanism is understood, the development of clinical interventions is not far away," Prather says.

The Arkansas research could also lead to safer 'strong' analgesics. New drugs could selectively enrich those receptor conformations responsible for opioids' therapeutic actions, while avoiding pathways mediating undesirable actions, such as tolerance and dependence. "Such an approach would also be applicable in the quest for other GPCR ligands with potential clinical application," Prather speculates.

Currently, however, inverse agonists' therapeutic benefits largely remain speculation. Indeed, whether exploitable differences between antagonists and inverse agonists exist is the field's most pressing unanswered question, says Richard Bond, University of Houston. "A lot of people feel the answer is yes, but irrefutable evidence is not there yet."

Mark Greener mgreener@the-scientist.com

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