Principles Of Receptor Pharmacology

Front 1

Agonists

Back 1

Agonists are compounds that bind to receptors and produce a biological response.

Front 2

Full agonists

Back 2

Full agonists are maximally effective at sufficiently high concentrations.

Front 3

Partial agonists

Back 3

Partial agonists are compounds that bind to receptors and exert an effect, but even at 100% full receptor occupancy will exert sub maximal response. In the presence of a full agonist, will act as an agonist.

Front 4

Antagonists

Back 4

Antagonists bind to receptors and and exert no activity by themselves, but block the effects of an agonist.

Front 5

Competitive antagonists

Back 5

Competitive antagonists compete with agonists for the binding site and their effects can be overcome with sufficiently high concentrations of agonists.

Front 6

Noncompetitive antagonists

Back 6

Noncompetitive antagonists interact with receptors in a manner that prevents agonists binding, no matter how high the concentration. Often they bind irreversibly, often covalent.

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Inverse agonists

Back 7

Inverse agonists stabilize the receptor such the they stop any baseline physiological activity.

Front 8

Efficacy

Back 8

Efficacy is the maximal response a drug can produce.

Front 9

Potency

Back 9

Potency refers to the dose of a drug required to give a certain response. More potent drugs will give a response at a lower concentration than a less potent drug. Given as an ED50 or EC50.

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Kd (equilibrium dissociation constant)

Back 10

When drug concentration is equal to Kd, half the receptors are occupied. The lower the Kd, the higher the drug affinity to the receptor.

Front 11

Scatchard plot

Back 11

A linear binding plot where the slope is = -1/Kd and the x-intercept is = Bmax, which is the total number of receptors.

Front 12

Desensitization

Back 12

Desensitization leads to receptors becoming refractory due to repeated drug exposure. Rapid desensitization is a result of phosphorylation and slower desensitization may be sequestration of receptors or reduced expression over time (downregulation). Conversely in response to an antagonist a target cell may upregulate receptors.

Front 13

Inhibition binding curves

Back 13

Many drugs can be screened for effectiveness by screening them against a radiolabeled ligand of known effectiveness. IC50 is the concentration of compound needed to inhibit 50% of binding.

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Occupancy assumption and spare receptors

Back 14

There appear to be spare receptors such that a drug can give a maximal response when only a fraction of receptors are occupied.

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Orphan receptors

Back 15

Orphan receptors are receptors with no known endogenous ligands.

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Endogenous ligands

Back 16

There are often multiple receptors that bind a single endogenous ligand. Endogenous ligands are often non selective and able to activate many different receptors to some degree. REMEMBER receptors are stereoselective.

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1. Channel-linked receptors (ionotropic)

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Binding leads to channel opening and hyperpolarization or depolarization on the order to MILLISECONDS, e.g. Nicotinic ACh receptor.

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2. G-protein coupled receptor (muscarinic)

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G protein activates and leads to secondary messengers resulting in cellular effects on the order of SECONDS, e.g. Muscarinic ACh receptor

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3. Kinase linked receptors

Back 19

Binding leads to protein phosphorylation and then cellular effects on the order of MINUTES e.g. insulin receptor

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4. Receptors linked to gene transcription (nuclear receptors)

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Binds to receptor in nucleus, leads to mRNA synthesis, protein synthesis, cellular effects on the order of HOURS e.g. estrogen receptor

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Biased ligands

Back 21

Some ligands can exert different effects on different receptor-activated pathways, they have the ability to stimulate a subset of a receptor's activities.