11.4: Molecular Pharmacodynamics

To talk more accurately about the action of drugs on a molecular level, it’s important to establish some of the vocabulary that is used in pharmacology. As we begin discussing the action and movement of molecules, it’s important to remember that the physical movement of molecules is more random than guided. When neurotransmitter molecules are released into the synapse, they move around in that space randomly. At many points in time, they float around the synapse, causing no effect. But sometimes, molecules will bump into a receptor, activating it as long as the molecule remains attached. Other times, those molecules will bump into reuptake proteins, large transmembrane proteins that decrease the concentration of neurotransmitters in the synapse by pulling the neurotransmitter back into the presynaptic axon terminal. And at other times, the molecule can even float outside of the synaptic space. Pharmacologists use the word stochastic to describe this randomness. The location of a molecule has no influence on where it will go next.

It is also helpful to become familiar with the dose-response curve, which is a graph that plots the activation of a receptor on the y-axis, and increasing dosage of a drug on the x-axis. In most cases, as neurotransmitter concentration increases, so does the activation of the corresponding receptor. The shape of the dose-response curve is described as sigmoidal, the S-shaped curve that is common to many fields of science, including ecology, microbiology, physics, and chemistry.

In molecular pharmacodynamics, we will describe three main categories of ligands, substances that are able to bind to receptors to form a ligand-receptor complex.

Figure 11.9 Generic dose response curve showing that drug effect (y-axis) increases as the dosage of drug (x-axis) increases.

1. Agonists are chemical substances that can activate receptors. Receptors themselves are large, transmembrane protein structures with a surface that is exposed to the extracellular side. On this exposed side, there is some three-dimensional arrangement of amino acids that the agonist is able to bind to. When the agonist-receptor complex is formed, the receptor physically changes conformation, which can then trigger a downstream reaction. In the case of an ionotropic receptor, the protein changes to either allow or hinder ion movement across the cell membrane. Nicotine is an example of an agonist that binds to ionotropic acetylcholine receptors. For metabotropic receptors, the activated agonist-receptor complex results in downstream activation of G-proteins, which then signal the cell to behave in a variety of ways. Morphine acts as an agonist at opioid receptors, which are metabotropic. The specific site on the receptor protein where agonists bind is called the orthosteric site, or active site.

The interaction between a receptor and an agonist can be described by the analogy of a lock and key. The receptor is represented by a lock. Receptors are large protein complexes that span the cell membrane, just like a lock sits at the interface between two rooms. Receptors have an outward facing side that responds to the presence of an agonist by physically changing shape, similar to the way a lock will physically change when the correct key is inserted into the keyhole. Finally, receptors are very specific and will only respond to chemical structures that “match” the active site - the lock won’t just open in the presence of any random key.

Agonists themselves can be divided into three different classes. A full agonist is a substance that can activate the receptor to the maximal degree at high concentrations. When we think of an endgenous neurotransmitter that is released by a neuron, such as glutamate, it activates the nearby glutamate receptors maximally. In a dose-response curve, full agonists are substances that set the 100% value. The phrase partial agonist is used to describe substances that can also activate the receptor by binding to the orthosteric site, but are unable to fully activate the receptor, even at increasingly higher doses. On a dose response curve, the partial agonist activates the receptor to a lesser degree than the full agonist. Some partial agonists can be used clinically for treating a variety of disorders including anxiety, psychosis, and chronic pain. Another class of agonists are the inverse agonists, which causes an opposite response as an agonist.

2. If agonists are the chemical substances that activate receptors, antagonists are the substances that prevent agonists from acting. More specifically, competitive antagonists are substances that bind to the orthosteric site, the same site on the receptor where an agonist would bind. Because competitive antagonists physically block the active site, and because molecules move around randomly, the presence of the antagonist can prevent the agonist from activating the receptor in a concentration dependent manner: The more antagonist present, the higher the concentration of agonist must be in the synapse for activation. Therefore, adding a competitive antagonist to the system will shift the dose response curve to the right.

Figure 11.10 Different classes of ligands and their action on the receptors.

Figure 11.11 Dose response curves for agonist and for agonist plus competitive antagonist.

One of the most well known competitive antagonists is the drug Narcan (naloxone) which inhibits certain opioid receptors. One reason opioid overdose can be fatal is the drugs are able to shut down CNS drive of the respiratory system through acting as agonists at opioid receptors. In order to treat the person in this situation, you will have to find a way to block the action of the opioid molecules that are still acting on the receptors. When Narcan is given via an IV injection or nasal spray, it works within minutes to block the action of opioid drugs that are affecting respiratory control, thus restoring normal breathing.

It is important to note that in the absence of an agonist, an antagonist alone will have no effect on cell excitation. Therefore, if an antagonist alone induces a change in some cellular property such as excitability, then it is reasonable to conclude that the cell is being acted upon by some agonist at rest.

Separate from agonists and antagonists are a different class of chemical substances called allosteric modulators that also interact with neurotransmitter signaling. These chemicals belong to a unique classification of substances distinct from agonists and antagonists. Instead of binding to the orthosteric active site, they target a different region of the receptor, a site called the allosteric site. The allosteric site generally can be found on the extracellular side of the receptor, and like the active site, consists of a special three-dimensional arrangement of amino acids. When allosteric modulators bind to the receptor, they change the potency of agonists that activate the receptor. They can either increase the action of the agonist (positive allosteric modulator, or PAM) or decrease the action (negative allosteric modulator, or NAM.) In either case, some agonist, either endogenous neurotransmitter or exogenously-introduced drug, must be present for the allosteric modulator to have any effect.

Figure 11.12 A receptor interacting with an allosteric modulator changes it’s response following agonist binding to the orthosteric site.

Allosteric modulators act at the level of the receptor to modulate excitability of the neurons. For example, consider an ionotropic receptor that allows Na+ to move across the cell membrane when an agonist is present. When a PAM is present simultaneously with the agonist, more Na+ ions will move across the receptor than if the agonist was acting alone. But, when a NAM is present with that same agonist, fewer Na+ ions will move across the membrane, resulting in decreased excitability.

Many of these allosteric modulators are used experimentally but some are used clinically. The most well known allosteric modulators are the barbiturates and benzodiazepines. Both are PAMs which act at the GABA receptor, meaning that when a benzodiazepine (like Valium) is present, the same amount of GABA will have a stronger effect. Since GABA is an inhibitory neurotransmitter, enhancing this inhibition of neural circuitry can be an effective way to decrease brain disorders that result from overexcitation of the brain: anxiety, epilepsy, and insomnia.

A single pharmaceutical agent can have different actions at different classes of receptors. For example, the common antipsychotic clozapine is an antagonist at some dopamine and serotonin receptors, while also acting as a partial agonist at a different population of serotonin receptors. In pharmacology, drugs with many sites of action are commonly called dirty drugs.