What are the characteristics and mechanisms of agonists, antagonists, partial agonists, and inverse agonists in mediating distinct biological activities through their target receptors?

From the Guidelines

Receptor ligands modulate biological activities through distinct mechanisms based on their interaction with target receptors, with agonists, antagonists, partial agonists, and inverse agonists producing different effects on morbidity, mortality, and quality of life. The characteristics and mechanisms of these ligands are crucial in understanding their therapeutic and adverse effects. Agonists, such as morphine, bind to receptors and activate them, producing a full biological response similar to the endogenous ligand, and are used to produce analgesia by binding to opioid receptors 1. Antagonists, such as naloxone, bind to receptors without activating them, blocking the binding site from agonists and preventing biological responses, and are used to reverse opioid overdose by preventing opioids from binding to their receptors 1.

Mechanisms of Action

• Agonists produce a full biological response by activating the receptor, with examples including morphine binding to opioid receptors to produce analgesia 1.
• Antagonists block the binding site from agonists, preventing biological responses, with examples including naloxone reversing opioid overdose 1.
• Partial agonists produce a submaximal response compared to full agonists, even at saturating concentrations, with examples including buprenorphine providing some pain relief while having a ceiling effect that reduces overdose risk 1.
• Inverse agonists produce an opposite effect to agonists by reducing constitutive receptor activity below baseline levels, with examples including flumazenil acting as an inverse agonist at GABA receptors, decreasing inhibitory neurotransmission.

Receptor Targets

• Mu opioid receptors are the primary target for opioid agonists, with binding resulting in strong analgesia mediated through brain mechanisms and intermediate analgesia via spinal mechanisms 1.
• Delta and kappa opioid receptors also contribute to analgesic effects, although to a lesser extent than mu opioid receptors 1.
• GABA receptors are targeted by inverse agonists, such as flumazenil, to decrease inhibitory neurotransmission.

Clinical Implications

• The use of agonists, antagonists, partial agonists, and inverse agonists has significant implications for morbidity, mortality, and quality of life, with careful consideration of the mechanism of action and receptor target necessary to minimize adverse effects and maximize therapeutic benefits 1.
• The selection of the appropriate ligand and receptor target is critical in minimizing the risk of overdose, addiction, and other adverse effects, while maximizing pain relief and improving quality of life.

From the FDA Drug Label

Buprenorphine Sublingual Tablets contain buprenorphine, a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). Neither losartan nor its principal active metabolite exhibits any partial agonist activity at the AT1 receptor, and both have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor

The different characteristics of agonists, antagonists, partial agonists, and inverse agonists are:

• Agonists: Bind to a receptor and produce a response, such as the full opioid agonists methadone and hydromorphone.
• Antagonists: Bind to a receptor but do not produce a response, such as buprenorphine at the kappa-opioid receptor.
• Partial agonists: Bind to a receptor and produce a response, but with a lower efficacy than a full agonist, such as buprenorphine at the mu-opioid receptor.
• Inverse agonists: Bind to a receptor and produce an opposite response, but this is not described in the provided drug labels.

These characteristics mediate distinct biological activities through their target receptors, such as:

• Mu-opioid receptor: targeted by buprenorphine as a partial agonist.
• Kappa-opioid receptor: targeted by buprenorphine as an antagonist.
• AT1 receptor: targeted by losartan as an antagonist. The proposed mechanisms include:
• Blocking the binding of angiotensin II to the AT1 receptor, as seen with losartan.
• Producing a dose-related response with a ceiling effect, as seen with buprenorphine. 2 3

From the Research

Characteristics of Agonists, Antagonists, Partial Agonists, and Inverse Agonists

• Agonists: These are drugs that bind to a receptor and cause a response by the cell. They have both affinity (the ability to bind to the receptor) and efficacy (the ability to produce a response) 4.
• Antagonists: These are drugs that bind to a receptor but do not elicit a response. Instead, they block the action of agonists. Antagonists can be further classified into competitive (surmountable) and non-competitive (insurmountable) antagonists 4.
• Partial Agonists: These are drugs that bind to a receptor and produce a response, but with lower efficacy than a full agonist. An example of a partial agonist is buprenorphine, which is a high-affinity partial agonist for the mu-opioid receptor 5, 6.
• Inverse Agonists: These are drugs that bind to a receptor and reduce the baseline activity of the receptor, even in the absence of an agonist. Inverse agonists require some preexisting level of receptor activity (or tone) to produce their effects 7.

Mechanisms of Action

• Agonists: Activate the receptor, leading to a biological response.
• Antagonists: Block the action of agonists by binding to the receptor without activating it.
• Partial Agonists: Activate the receptor, but with lower efficacy than a full agonist, resulting in a reduced biological response.
• Inverse Agonists: Reduce the baseline activity of the receptor, leading to a decrease in the biological response.

Receptor Targets

• Mu-opioid receptor: Targeted by agonists (e.g. morphine, fentanyl), partial agonists (e.g. buprenorphine), and antagonists (e.g. naloxone) 5, 6, 8.
• Other receptors: Targeted by various agonists, antagonists, partial agonists, and inverse agonists, depending on the specific receptor and drug.

Proposed Mechanisms and Biological Activities

• Buprenorphine, a partial agonist, suppresses opioid withdrawal and craving, reduces illicit opioid use, and blocks exogenous opioid effects, including respiratory depression, by targeting the mu-opioid receptor 5.
• Naloxone, an antagonist, reverses opioid overdose by blocking the action of opioid agonists at the mu-opioid receptor 8.
• Inverse agonists, such as negative allosteric modulators, can reduce the baseline activity of the mu-opioid receptor, potentially preventing opioid overdose deaths 8.