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In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. See also Signal transduction.
Ligands include:
Substrates
Inhibitors
Activators. Enzyme activators are molecules that bind to enzymes and increase their activity.
- An example of an enzyme activator working in this way is fructose 2,6-bisphosphate, which activates phosphofructokinase 1 and increases the rate of glycolysis in response to the hormone glucagon.
- Hexokinase-I (HK-I) is an enzyme activator because it draws glucose into the glycolysis pathway. Its function is to phosphorylate glucose releasing glucose-6-phosphate (G6P) as the product. HK-I not only signals the activation of glucose into glycolysis but also maintains a low glucose concentration to facilitate glucose diffusion into the cell.
Agonists. A ligand that can bind to and alter the function of the receptor that triggers a physiological response is called a receptor agonist.
Endogenous agonists:
In general, receptors for small molecule neurotransmitters such as serotonin will have only one endogenous agonist, but often have many different receptor subtypes (e.g. 13 different receptors for serotonin). On the other hand, neuropeptide receptors (e.g. opioid receptors) tend to have fewer subtypes, but may have several different endogenous agonists. This allows for a high degree of complexity in the body's signalling system, with different tissues often showing quite distinct responses to a particular ligand.
Exogenous agonists - Drugs.
Full agonists bind to and activate a receptor with the maximum response that an agonist can elicit at the receptor. One example of a drug that can act as a full agonist is isoproterenol, which mimics the action of adrenaline at β-adrenoreceptors (see Beta-1 Adrenergic receptor. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors. See
Co-agonist works with other co-agonists to produce the desired effect together. NMDA receptor (see Ionotropic Glutamate Receptors) activation requires the binding of both glutamate, glycine and D-serine co-agonists. Calcium can also act as a co-agonist at the IP3 receptor.
Selective agonist is selective for a specific type of receptor. E.g. buspirone is a selective agonist for serotonin 5-HT1A (see 5-hydroxytryptamine receptor.
Partial agonists (such as buspirone, aripiprazole, buprenorphine, or norclozapine) also bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist, even at maximal receptor occupancy. Agents like buprenorphine are used to treat opiate dependence for this reason, as they produce milder effects on the opioid receptor (see μ Opioid Receptors) with lower dependence and abuse potential. Examples of ligands activating peroxisome proliferator-activated receptor gamma as partial agonists are honokiol and falcarindiol.
Inverse agonist is an agent that binds to the same receptor binding-site as an agonist for that receptor and inhibits the constitutive activity of the receptor. The opioid antagonists naloxone and naltrexone are also partial inverse agonists at μ Opioid Receptors. Nearly all antihistamines acting at H1 receptors and H2 receptors have been shown to be inverse agonists. The beta blockers carvedilol and bucindolol have been shown to be low level inverse agonists at beta adrenoreceptors.
Superagonist is a term used by some to identify a compound that is capable of producing a greater response than the endogenous agonist for the target receptor. It might be argued that the endogenous agonist is simply a partial agonist in that tissue. acts as a 1alpha,25(OH)(2)D(3) superagonist of Vitamin D on Vitamin D receptor and exhibits both antiproliferative and prodifferentiating properties in vitro.
A physiological agonist is a substance that creates the same bodily responses but does not bind to the same receptor.
Examples of agonists:
- acts as a 1alpha,25(OH)(2)D(3) superagonist of Vitamin D on Vitamin D receptor and exhibits both antiproliferative and prodifferentiating properties in vitro.
- in Transport inhibitor response 1 (3c6o). Water molecules are shown as red spheres.
- of human Bile acid receptor ligand-binding domain (deeppink) complex with non-steroidal agonist, nuclear receptor coactivator 1 peptide (cyan) and sulfate ions (PDB entry 3ruu). [1]
Ligands that bind to a receptor but fail to activate the physiological response are receptor antagonists.
Competitive antagonists bind to receptors at the same binding site (active site) as the endogenous ligand or agonist, but without activating the receptor. Agonists and antagonists "compete" for the same binding site on the receptor. Naloxone (also known as Narcan) is used to reverse opioid overdose caused by drugs such as heroin or morphine (μ Opioid Receptors).
- participates directly in agonist/competitive antagonist binding, affects activation gating, and is the portion that forms the 'middle' layer.
- in the structure of Glutamate receptor (GluA2).
- The small molecule [2], was studied as a treatment for stroke because it had demonstrated neuroprotective efficacy in experimental models of stroke and tolerability in healthy volunteers; however, in a multicenter, double-blind, randomized, placebo-controlled phase II trial, it was found to have significant sedative effects in patients with acute stroke which precludes its further development as a neuroprotective agent[3].
Physiological antagonists, substances that have opposing physiological actions, but act at different receptors. For example, histamine lowers arterial pressure through vasodilation at the histamine H1 receptor, while adrenaline raises arterial pressure through vasoconstriction mediated by alpha-adrenergic receptor activation.
