A pharmacological paradox: may a neutral antagonist shift an agonist concentration-response curve to the left?

Abstract

It is generally accepted that the presence of a competitive antagonist shifts an agonist concentration-response curve to the right. However, this may not always be the case: The concentration-response curve of an inverse receptor agonist may be shifted to the left by a neutral antagonist; a condition, which can be hypothetically explained by the assumption of both negative cooperativity of dimeric receptors plus a receptor reserve.The presence of a competitive antagonist usually shifts an agonist concentration-response curve to the right. As it can be learned from the paper of Jergas et al. By definition, a neutral competitive antagonist only changes the affinity of an agonist. Nevertheless, under the following assumptions, such a sole decrease in the agonist affinity can explain an increase in the potency of an inverse agonist, as observed by Jergas et al. (2014), i.e., a shift to the left of its concentration-response curve.