Antagonists and Agonists Summary

Antagonists

• An antagonist is a substance that doesn't provoke a biological response itself upon binding to a receptor. Instead, it functions to block or reduce responses mediated by agonists. This inhibitory action is crucial in regulating receptor activity and downstream signaling pathways.

• Antagonists mediate their effects through various mechanisms:

  • Binding to the active site: Some antagonists compete directly with agonists for the active site on the receptor. By occupying this site, they prevent agonists from binding and initiating a response.

  • Binding to allosteric sites on receptors: Allosteric antagonists bind to a site on the receptor distinct from the agonist binding site. This binding induces a conformational change in the receptor protein, which alters the receptor's affinity for the agonist or impairs its ability to activate downstream signaling pathways.

  • Interacting at unique binding sites not normally involved in the biological regulation of the receptor's activity: Certain antagonists may interact with unique binding sites on or near the receptor, leading to indirect modulation of receptor function.

• Antagonist activity can be further classified as competitive or non-competitive, depending on the nature of the antagonist-receptor binding:

  • Competitive antagonism involves the antagonist binding reversibly to the same site as the agonist. The level of inhibition depends on the relative concentrations of the agonist and antagonist.

  • Non-competitive antagonism occurs when the antagonist binds irreversibly to the receptor or to a different site that prevents receptor activation. In this case, increasing the concentration of the agonist cannot overcome the inhibition.

• Antagonist activity can also be characterized as reversible or irreversible, based on the longevity of the antagonist-receptor complex. This longevity is determined by the nature of the antagonist-receptor binding:

  • Reversible antagonists bind to the receptor through weak, non-covalent interactions, allowing for rapid dissociation and restoration of receptor function once the antagonist is removed.

  • Irreversible antagonists form strong, covalent bonds or exhibit very slow dissociation from the receptor, resulting in prolonged inhibition that may require the synthesis of new receptors to restore normal function.

Competitive Antagonists

• Competitive antagonists bind to the same receptor site as an agonist, competing directly for occupancy of the binding pocket.

• Competitive reversible antagonist- Inhibition caused by a competitive reversible antagonist is reversible and can be overcome by increasing the concentration of the agonist.

  • Maximal response for the agonist can still be achieved, but it requires a higher concentration of the agonist than in the absence of the antagonist.

  • Example: EC{50A} < EC{50B}, where EC{50A} represents the concentration of agonist needed for 50% maximal effect without the antagonist, and EC{50B} represents the concentration needed with the antagonist.

  • There is typically no significant depression in maximal response (E[max]); the same maximal effect can be reached with a sufficient concentration of the agonist.

  • Agonist dose-response curve is shifted to the right, indicating a decrease in potency.

  • Agonist potency is controlled/affected; the presence of the antagonist effectively reduces the potency of the agonist.

  • Prazosin acts at α-adrenergic receptors and is used to treat conditions such as high blood pressure, anxiety, panic, and post-traumatic stress disorder (PTSD). By blocking α-adrenergic receptors, it reduces vasoconstriction and lowers blood pressure.

• Competitive irreversible antagonist- Binds to the same receptor site as an agonist, but forms a stable, irreversible bond.

  • Inhibition is irreversible and cannot be overcome by increasing agonist concentration, as the antagonist permanently occupies the binding site.

  • Covalent bonds are often formed, or dissociation is very slow, leading to a stable antagonist-receptor complex.

  • The only mechanism the body has for overcoming the block is to synthesize new receptors, as existing receptors are permanently occupied.

  • Useful as experimental tools for investigating receptor functions, as they allow researchers to selectively block specific receptors and study the effects of their inactivation.

  • Example: Phenoxybenzamine at α-adrenergic receptors. It is used to manage hypertension and sweating associated with pheochromocytoma.

Non-competitive Antagonists

• Non-competitive antagonists do not bind to the same receptor site as the agonist; instead, they bind to a different (allosteric) site on the receptor.

• Decreases the affinity of the receptor for the agonist: causing “allosteric inhibition,” which reduces the likelihood of the agonist binding and activating the receptor.

• Prevents conformational changes in the receptor that are required for receptor activation after the agonist binds: also through “allosteric inhibition,” which impairs the receptor's ability to transduce the signal even when the agonist is bound.

• Alternatively, interferes with the chain of events that leads to the production of a response by the agonist. This can involve disrupting intracellular signaling pathways or affecting downstream effector molecules.

• Inhibition cannot be overcome by increasing agonist concentration (irreversible), since the antagonist's effect is independent of agonist binding.

• Agonist maximal response will be depressed, as the antagonist reduces the overall capacity of the system to respond to the agonist.

• Agonist potency may or may not be affected, depending on the specific mechanism of non-competitive antagonism.

• Ketamine is a non-competitive NDMA receptor antagonist. It is used as an anesthetic and analgesic and also shows promise in treating depression.

Agonists

• Full Agonist: A drug with high efficacy that produces a maximal tissue response when bound to its receptor.

• Partial Agonist: A drug with an intermediate level of efficacy, such that even when 100% of the receptors are occupied, the tissue response is submaximal. Its efficacy is less than that of a full agonist.

Pharmacological Antagonists

• Drugs that bind to receptors but do not activate them like agonists and, therefore, do not alter receptor function; instead, they block or reduce agonist-mediated responses.

• These antagonists may block the ability of agonists to bind to the receptor by competing for the same receptor site, thus preventing the agonist from exerting its effects. Alternatively, they may bind to another site on the receptor that blocks the action of the agonist through allosteric modulation.

• In both cases, the biological actions of the agonist are prevented, leading to a reduction in the overall response.

Chemical Antagonists

• A drug that antagonizes the action of a second drug by binding to and inactivating the second drug directly via chemical interaction.

• Example: protamine (a positively charged protein at physiologic pH) binds to (sequesters) heparin (a negatively charged anticoagulant), making it unavailable for interactions with proteins involved in the formation of blood clots. This interaction neutralizes the anticoagulant effects of heparin.

Physiological Antagonists

• A substance that produces effects counteracting those of another substance (a result similar to that produced by an antagonist blocking the action of an agonist at the same receptor) by using a mechanism that does not involve binding to the same receptor.

• For instance, epinephrine raises arterial pressure through vasoconstriction mediated by A1-adrenergic receptor activation, in contrast to histamine, which lowers arterial pressure via vasodilation. Epinephrine and histamine act on different receptors to produce opposing effects on blood pressure.

• Thus, despite not being true antihistamines because they do not bind to and block the histamine receptor, epinephrine and other such substances are physiological antagonists to histamine. Their effects oppose those of histamine through different physiological pathways.

Partial Agonists

• A drug with an intermediate level of efficacy, such that even when 100% of the receptors are occupied, the tissue response is submaximal. Partial agonists cannot produce the same maximal response as full agonists, regardless of concentration.

• Partial agonists competitively inhibit the responses produced by full agonists. By binding to the same receptors, they prevent full agonists from exerting their maximal effects.

Full & Partial Agonists

• Pindolol, a β-adrenoceptor "partial agonist," may act as either an agonist (if no full agonist is present) or as an antagonist (if a full agonist such as isoproterenol is present). Its effects depend on the presence and concentration of other agonists.

Opioids

• Examples:

  • Morphine: A full opioid agonist used for pain relief.

  • Methadone: A full opioid agonist used for pain management and opioid maintenance therapy.

  • Naltrexone: An opioid antagonist used to reverse the effects of opioids and prevent relapse in opioid use disorder.

  • Buprenorphine: A partial opioid agonist used for pain relief and opioid maintenance therapy. It produces a submaximal effect compared to full agonists.

Opioid Treatment

• Comparison of intrinsic activity vs. log dose of opioid for:

  • Full Agonist (Methadone): Produces a maximal response at sufficient doses.

  • Partial Agonist (Buprenorphine): Produces a submaximal response, even at high doses.

  • Antagonist (Naltrexone): Has no intrinsic activity and blocks the effects of agonists.

Summary

• Agonists: Substances that bind to receptors and activate them, leading to a biological response.

• Antagonists: Substances that block or reduce agonist-mediated responses by binding to receptors without activating them.

• Dose response curve: Illustrates the relationship between drug dose and the resulting effect, showing potency and efficacy.

• Potency: A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity.

• Maximal and submaximal responses: Refer to the maximum possible effect a drug can produce (full agonist) versus a lesser effect even at full receptor occupancy (partial agonist).

• Full and partial agonists: Full agonists produce maximal responses, while partial agonists produce submaximal responses.

• Competitive reversible antagonists: Bind reversibly to the same site as the agonist and can be overcome by increasing agonist concentration.

• Competitive irreversible antagonists: Bind irreversibly to the same site as the agonist, and their effects cannot be overcome by increasing agonist concentration.

• Allosteric sites and allosteres: Allosteric sites are different binding locations on the receptor that can modulate receptor activity when bound by allosteric modulators (allosteres).

• Chemical, physiological, and pharmacological antagonists: Chemical antagonists inactivate drugs directly, physiological antagonists use different pathways to produce opposing effects, and pharmacological antagonists block receptors.