Inverse agonism or neutral antagonism at G-protein coupled receptors: a medicinal chemistry challenge worth pursuing?

The identification of constitutive, or intrinsic, activity of G-protein coupled receptors has had major impact on receptor theory, the identification of agents that inhibit this ligand-independent receptor activity has led, in turn, to the concept of inverse agonism. It has subsequently emerged that the majority, around 85%, of all known G-protein coupled receptor antagonists are, in fact, inverse agonists. Agents that affect only ligand-dependent receptor activation, i.e. have no effect on constitutive receptor signalling, are termed neutral antagonists and turn out to be relatively rare in pharmacology. Is this relevant for medicinal chemistry? That question is difficult to answer with certainty because there has been little or no effort to understand the structure activity relationships of neutral antagonist vs. inverse agonist molecules. In this review, we suggest that these pharmacological differences may well be translated to differential effects in the whole animal and in medicine. We argue that having either option to inhibit a particular receptor may reveal differences in efficacy and tolerability thus increasing the potential value of a G-protein coupled receptor inhibitor programme. However, since inverse agonists appear to constitute a default inhibitor mode, a systematic survey of the structure activity relationships around what makes a neutral antagonist will be an essential first step towards this goal.