What is a partial agonist?

From the Guidelines

A partial agonist is a drug that binds to a receptor but elicits a partial response compared to a full agonist, as seen with buprenorphine, a partial mu opioid receptor agonist. This characteristic allows partial agonists to produce a limited effect, typically between 20-80% of the maximum possible effect, even at maximum concentration 1.

Key Characteristics of Partial Agonists

• Bind to a receptor but produce only a partial response
• Activate the receptor with reduced efficacy
• Can function as both agonists and antagonists depending on the surrounding conditions
• Useful for treating addiction, psychiatric disorders, and other conditions where modulating receptor activity is beneficial

Examples of Partial Agonists

• Buprenorphine, used to treat opioid dependence and pain
• Aripiprazole, used as an antipsychotic
• Varenicline (Chantix), used for smoking cessation In the context of opioid receptors, buprenorphine is a notable example of a partial agonist, as it is utilized in the treatment of pain, opioid use disorder, or both, and its perioperative management has been the subject of recent clinical practice advisories 1.

Clinical Value of Partial Agonists

• Can provide some receptor activation in the absence of a full agonist
• Act as competitive antagonists by blocking receptor sites in the presence of high levels of a full agonist
• Useful for modulating receptor activity rather than fully activating or blocking it, making them beneficial for treating various conditions.

From the FDA Drug Label

Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Buprenorphine hydrochloride is a partial opioid agonist.

A partial agonist is a drug that binds to a receptor but elicits a response lower than the maximum response that can be produced by full agonist drugs. In the case of buprenorphine, it is a partial opioid agonist, meaning it binds to opioid receptors but produces a lower response than full opioid agonists, such as morphine. 2 2

From the Research

Definition of Partial Agonist

• A partial agonist is a substance that elicits a lower maximal response of a particular biological system than a defined standard, typically a full agonist 3.
• Partial agonism is relative and depends on the definition of a standard substance that achieves a 'full' maximal response 3.
• Partial agonists can produce a range of effects, from minimal to significant, but never reach the maximum effect of a full agonist 3, 4.

Mechanisms of Partial Agonism

• Receptor-related mechanisms: the agonist-receptor complex exists in several conformational states, and only one or a few activate the cell signaling pathway 3.
• Mechanisms based on the efficacy of the stimulus-response coupling: the efficacy is proportional to the sum of probabilities that receptors in individual states activate the cell-signaling pathway 3.
• Partial agonists may contain both agonistic and antagonistic moieties, which can affect their ability to activate receptors 4.

Examples of Partial Agonists

• Buprenorphine is a partial agonist at the μ-opioid receptor, with high binding affinity but lower maximal response compared to full agonists 5, 6.
• Other partial agonists, such as butorphanol and nalbuphine, have been studied for their effects on opioid addiction and analgesia 6.

Relationship with Antagonists

• Antagonists can inhibit agonist-stimulated responses by binding to orthosteric or allosteric sites, and may exhibit partial agonist activity in certain contexts 7.
• The relationship between antagonists and partial agonists is complex and influenced by factors such as constitutive activity of GPCRs, intrinsic activity, and differences in binding sites 7.