This document discusses different types of receptor ligands including partial agonists, inverse agonists, and antagonists. It explains that partial agonists have full receptor affinity but lower intrinsic activity than full agonists, producing both direct and competitive antagonist effects. Inverse agonists also have full receptor affinity but their intrinsic activity is negative, producing effects opposite to agonists by reversing elevated basal receptor responses. The document notes inverse agonism can be demonstrated more clearly when the basal receptor response or assay sensitivity is increased. It concludes by discussing the in vivo effects of various antagonists and how they can potentiate other ligands through multiple mechanisms of action.

1. Chapter : 4
Drug antagonism
Partial, Inverse Agonists and
Antagonist effects In Vivo
2018B003
Md. Rasheduzzaman Jony
Inje University, College of Medicine1

2. Agonist vs Antagonist
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3. Partial agonist
› These ligands have full affinity to receptor but with low
intrinsic activity and its less than 1.
Ex: Pindolol (β-blocker), Pentazocine (Opioids)
› Partial agonist = Affinity + IA (0 to<1)
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4. The partial agonist produces a direct response due to a low level of positive efficacy and it also shifts
the dose response curve to the agonist to the right. This competitive antagonist effect is the result of
competition between the high efficacy agonist and lower efficacy partial agonist.
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5. Inverse agonist
› These have full affinity towards the receptor but intrinsic
activity is zero to -1.
Ex; ß-Carboline is inverse agonist for Benzodiazepines
receptors.
› Produces effect is just opposite to that of agonist.
› Inverse agonist = Affinity + IA (0 to -1)
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6. If the receptor system is constitutively active then the baseline response will be spontaneously elevated. The
inverse agonist produces a direct reversal of this elevated basal response due to a low level of negative efficacy;
the inverse agonist also shifts the dose response curve to the agonist to the right.
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7. Inverse agonism discovery
• Elevation of the basal response through changes in
ionic media revealed a clear negative response to the
peptide ICI174.
• The weakly positive response to MR2266 was not
obvious until the basal response and assay sensitivity
were elevated to a higher level with 150 mM KCl.
• Increased sensitivity of the assay is optimal for
demonstrating positive agonism.
• Increased basal response is optimal for showing
inverse agonism.
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8. Inverse agonist mechanism
Inverse agonists selectively bind to the inactive state of the
receptor. If any receptor happens to be in an active
state spontaneously, then an inverse agonist will
reverse the resultant constitutive activity.
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9. The in vivo effects of various antagonists
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10. Multiple response
• Potentiates acetylcholine by blocking
acetylcholinesterase enzyme
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