Pharmacologic Agonists
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Overview
- An agonist binds to a receptor and activates it.
- We specifically address: full agonists, partial agonists, and inverse agonists.
Constitutive Activity
- At baseline, the receptor exhibits constitutive activity, which means that it naturally flips between its active and inactive states to produce a basal level of effect (a low level of activity).
Full Agonist
- The full agonist produces the maximal effect possible; full activation of the receptors it binds to.
Full Agonist Example: Dopamine Agonists (eg, Pramipexole & Ropinirole)
- Consider Parkinson’s disease, in which our goal is to increase dopamine levels within the brain.
- We can administer levodopa, which acts as replacement therapy for the loss of naturally occurring dopamine.
- Or we can administer a full dopamine agonist, such as pramipexole or ropinirole. These drugs mimic the molecular structure of dopamine, which allows them to bind to various dopamine receptors and activate them. They are considered direct-acting because they act directly at the dopamine receptor binding site.
- Alternatively, we can administer an indirect-agonist, such a monoamine oxidase inhibitor (eg, selegiline or rasgiline), which does not directly act at the binding site but rather acts indirectly; it increases levels of dopamine by preventing its breakdown.
Partial Agonist
- A partial agonist also acts directly at the receptor but only produces a partial response.
- In the presence of a full agonist, a partial agonist can actually reduce the overall response because the partial agonist competes with the full agonist for receptor binding sites.
Partial Agonist Example: Buprenorphine
- A great example of this is buprenorphine, which is a partial agonist at the mu receptor (an opioid receptor): it produces less of a response than other opioids, like morphine.
- Buprenorphine is used to prevent morphine abuse because it is far more potent than morphine for the mu receptor. So even if a patient takes morphine , the receptors are already bound up by the less efficacious buprenorphine.
Inverse Agonist
- An inverse agonist reduces the activity to less than the constitutive level; it reduces its the effect below the unbound state of the receptor.