Negative efficacy

The discovery of constitutive receptor activity uncovered a major new idea in receptor pharmacology namely, the concept of negative efficacy and inverse agonism. 

Negative efficacy, by definition, efficacy is that property of a molecule that causes the receptor to change its behavior toward the biological host. Negative efficacy refers to the property of selective affinity of the molecule for the inactive state of the receptor this results in inverse agonism. Negative efficacy causes the active antagonism of constitutive receptor activity but is only observed in systems that have a measurably elevated basal response due to constitutive activity. It is a property of the molecule and not the system. 

Braestrup C, Nielsen M, HonoreT, etal Benzodiazepine receptor ligands with positive and negative efficacy. Neuropharmacology 22 1451—1457, 1983... 

Suppose that L combines only with the inactive, R, form. Then the presence of L, by promoting the formation of LR at the expense of the other species, will reduce the proportion of receptors in the active, R, state. L is said to be an inverse agonist or negative antagonist and to possess negative efficacy. If, in contrast, L combines with the R form alone, it will act as a conventional or positive agonist of very high intrinsic efficacy. 

The most striking difference concerned some A-arylpi-perazines which displayed modest negative efficacy (e.g.,... 

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