Negative antagonists

If L combines only with R, then the presence of L will reduce the proportion of active receptors. L is said to be an inverse agonist or negative antagonist. If L combines with R there will be an increase in active receptors and so L will behave as a conventional agonist. Where L has equal affinity for R and R, it will not affect the fraction of receptors in the active state. However, it will reduce the binding of either a conventional or an inverse agonist, and so will behave as an antagonist. 

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. 

An inverse agonist is a drug which acts at the same Inverse agonist receptor as that of an agonist, yet produces an opposite effect. Also called negative antagonists. 

Samama, P. Pei, G. Costa, T. Cotecchia, S. Lefkowitz, R.J. Negative antagonists promote an inactive conformation of the beta 2-adrenergic receptor. Mol. Pharmacol. 1994, 45, 390-394. 

Bilsky EJ, Bernstein RN, Wang ZJ, Sadee W, Porreca E (1996) Effects of neutral and negative antagonists and protein kinase inhibitors on acute morphine dependence and antinociceptive tolerance in mice. J Pharmacol Exp Ther 277 484 90... 

With the ability to measure constitutive receptor activity, some compounds like the )32-adrenoceptor antagonist, ICI 118551, were found to inhibit constitutive activity, thus functioning as an inverse agonist or negative antagonist (50). The concept of an inverse agonist was first proposed by Braestrup et al. in their studies of the GABA /BZ receptor complex (51). 

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