Receptors Mode of Action

1. Protein Receptor Agonist: A protein receptor agonist is a molecule that binds to a specific receptor site on a cell surface or within a cell and activates the receptor, leading to a biological response. Agonists mimic the action of endogenous signaling molecules, such as hormones or neurotransmitters, and promote cellular responses by initiating downstream signaling pathways. This activation triggers a series of events that regulate various physiological processes within the body. Superagonists are an agonist whose efficacy exceeds that of the endogenous agonist¹.

2. Protein Receptor Antagonist: A protein receptor antagonist is a molecule that binds to a specific receptor site without activating it, thereby blocking the receptor from being activated by agonists. Antagonists prevent the biological response that would normally occur upon receptor activation. They are often used as therapeutic agents to inhibit the effects of endogenous molecules or other agonists, making them valuable in the treatment of various diseases and conditions².

3. Partial Agonist: A partial agonist is a molecule that binds to a receptor and activates it, but only partially induces the biological response compared to a full agonist. Partial agonists have both agonistic and antagonistic properties, as they can activate the receptor to a certain extent while also inhibiting the action of full agonists when present. The efficacy of partial agonists is lower than that of full agonists³.

4. Inverse Agonism: Inverse agonism is a pharmacological concept related to receptor activity, particularly in the context of G-protein coupled receptors (GPCRs). Inverse agonists are compounds that, when binding to a receptor, stabilize the inactive conformation of the receptor and reduce its basal or constitutive activity. Unlike neutral antagonists, which simply block the receptor without affecting its basal activity, inverse agonists actively reduce the receptor's signaling activity below the baseline level observed in the absence of any ligand⁴.

5. Biased Agonism: Biased agonism, also known as functional selectivity or ligand bias, is a phenomenon where a ligand (agonist or partial agonist) preferentially activates one signaling pathway downstream of a receptor over others. Different signaling pathways can be activated by the same receptor, leading to diverse physiological responses. Biased agonists selectively activate one pathway while having reduced or no activity on others. This concept has important implications for drug development, as it allows for the development of drugs that target specific therapeutic pathways while avoiding unwanted side effects⁵.

Figure 1: Expected target response.

6. Positive Allosteric Modulators (PAMs): Positive allosteric modulators (PAMs) are molecules that bind to a specific site on a receptor distinct from the active site (the orthosteric site) and enhance the receptor's response to its endogenous ligand (usually an agonist). Unlike agonists, PAMs do not activate the receptor directly. Instead, they potentiate the effect of the agonist by either increasing the affinity of the receptor for the agonist or stabilizing the active conformation of the receptor, making it more responsive to the agonist. Positive allosteric modulation allows for fine-tuning of receptor activity and can lead to more specific and safer drug effects⁶.

7. Negative Allosteric Modulators (NAMs): Negative allosteric modulators (NAMs) are molecules that bind to a specific site on a receptor and decrease the receptor's response to its endogenous ligand (usually an agonist) without directly activating the receptor. NAMs can reduce the affinity of the receptor for the agonist or stabilize the inactive conformation of the receptor, making it less responsive to the agonist. By inhibiting receptor activity, NAMs can counteract the effects of agonists and provide a way to regulate excessive signaling, which is often associated with diseases and disorders⁷.

Both positive and negative allosteric modulators offer opportunities for designing drugs with high specificity and reduced side effects, making them important targets in drug discovery and development efforts.

References:

1 - Lefkowitz RJ. (2004). Historical review: A brief history and personal retrospective of seven-transmembrane receptors. Trends Pharmacol Sci, 25(8), 413-422. (DOI: 10.1016/j.tips.2004.06.006).

2 - Kenakin T. (2004). Principles: Receptor theory in pharmacology. Trends Pharmacol Sci, 25(4), 186-192. (DOI: 10.1016/j.tips.2004.02.012).

3 - Christopoulos A. (2002). Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat Rev Drug Discov, 1(3), 198-210. (DOI: 10.1038/nrd746).

4 - Kenakin T. (2019). The effective application of biased signaling to new drug discovery. Mol Pharmacol, 96(5), 598-608. (DOI: 10.1124/pr.118.016790).

5 - Kenakin T. (2011). Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br J Pharmacol, 165(6), 1659-1669. (DOI: 10.1111/j.1476-5381.2011.01749.x).

6 - Conn PJ, Christopoulos A, Lindsley CW. (2009). Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat Rev Drug Discov, 8(1), 41-54. (DOI: 10.1038/nrd2760).

7 - Kruse AC, Weiss DR, Rossi M, et al. (2013). Muscarinic receptors as model targets and antitargets. Structure, 21(11), 1892-1904. (DOI: 10.1124/mol.113.087551).

8 - Remesic M, Hruby VJ, et al. (2017) Recent advances in the realm of allosteric modulators for opioid receptors for future therapeutics. ACS Chem Neurosci. Jun 21; 8(6): 1147–1158. (DOI: 10.1021/acschemneuro.7b00090).