All of the following are features of inverse agonism except -
Ans. is 'b' i.e., An inverse agonist has a higher affinity for the active form of receptor as compared to the inactive form o An inverse agonist has higher affinity for inactive confirmation (Ri) of receptor and will produce an effect opposite to that of an agonist; examples of such inverse agonists at G-protein coupled receptors are famotidine, losaon, metoprolol, risperidone. For option a & c you should know the following impoant facts: o As I have explained in previous explanation; usually inactive confirmation (Ri) of receptor predominate in the absence of agonist and the signal output is low. If the preexisting or basal equilibrium for unliganded receptors lies far.in the direction of inactive confirmation (Ri), it may be very difficult to demonstrate inverse agonism because receptors are already existing in inactive state and inverse agonist has nothing to do (inverse agonist shifts the equilibrium towards inactive confirmation, but the receptors are already existing in inactive confirmation). o Some times receptor can adopt active confirmation (in the absence of agonist) that can produce a cellular response spontaneously -3 constitutional spontaneous activity without an agonist. In this situation, the tissue behaves as if there were agonist present. In this situation. i) Inverse agonism can be easily observed as inverse agonist shifts the equilibrium towards inactive state. So, it inhibits the agonist-independent constitutional signaling which can be easily observed. ii) Antagonist will have no effect as antagonist has equal affinity for active (Ra) as well as inactive (Ri) state of receptor. So, the equilibrium will remain the same. iii) It will be difficult to demonstrate activity of agonist as agonist shifts the equilibrium towards active confirmation, but the receptors are already existing in active confirmation (constitutional spontaneous active state). o Now you can easily understand: A. In usual resting stage (when inactive confirmation of receptor predominates in the absence of agonist) i) Agonism can be observed easily ii) Antagonism can be observed easily Inverse agonism is difficult to observe B. In stage of spontaneous constitutional activity when active confirmation predominates in the absence of agonist (It may sometime occurs due to rnutation -*constitutively active mutant receptors) i) Agonism is difficult to observe ii) Antagonist has no effect Inverse agonism can be observed easily
It is easier to observe inverse agonism if there is sufficient constitutive activity of receptor in the absence of agonist
An inverse agonist has a higher affinity for the active form of receptor as compared to the inactive form
If the equilibrium of receptor state lies in the direction of inactive confirmation in the absence of a ligand, it may be impossible to demonstrate inverse agonism
Famoti di n e and losaan can be considered inverse agonists