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Rethinking drug action

Over the last few years, pharmacologists have abandoned the traditional view of drug action in favour of a much more subtle, sophisticated theory. Even the terms used to classify certain drugs have changed. Mark Greener reviews this new view to help nurses better understand how current drugs act and introduces some ways in which the theory will lead to new treatments

Mark Greener
Freelance Medical Writer, Journalist
and Editor
Former Research Pharmacologist

For generations, pharmacologists attached one end of a small sample of muscle - a guinea pig ileum, for example - to a pressure gauge and tied the other end to a fixed point in a tissue bath. Apply adrenaline and the muscle contracts. Pretreatment with propranolol partially or totally (depending on the relative concentrations) blocks the response to adrenaline.
The classic theory essentially regards receptors as passive “locks” into which agonists and antagonists fit as “keys”. Adrenaline is an agonist. In other words, it binds to and stimulates receptors, mimicking the effect of the neurotransmitter (noradrenaline or adrenaline in this case). Propranolol is an antagonist. It binds to, but does not stimulate, the receptor. Antagonists block endogenous ligands from reaching the receptor. (Ligand refers to a chemical - neurotransmitter, hormone, drug, etc - that binds to a receptor.)
The size of the response depends on three factors. First, the number of receptors occupied by the agonist and the antagonist. Second, the strength of the bond between the drug and receptor. Pharmacologists describe the bond's strength as the drug's “affinity”. Third, each drug has an “intrinsic activity” - its ability to activate a receptor. Pharmacologists regard intrinsic activity as a spectrum with full agonists and full antagonists at opposing ends.
After running countless experiments in organ baths, pharmacologists realised that some drugs seem to act as both agonists and antagonists in the same tissue. This led to the idea of partial agonism. A full agonist has an intrinsic activity of 100%. A full antagonist has no intrinsic activity. A partial agonist shows an intrinsic activity between these extremes. If a drug's intrinsic activity is 50%, the partial agonist effectively acts as an antagonist that halves the response.
The treatment of substance abuse offers a striking example of the application of receptor theory to a clinical problem. After taking a drug, the user experiences a high or another “benefit”. The regular user experiences craving for the drug when blood levels of the drug fall. They use the drug, top up their blood levels, which recreates the high and reinforces the drug abuse. A full agonist would recreate the high. A full antagonist would prevent the high, but trigger craving and withdrawal. Partial agonists balance these competing actions.
For example, buprenorphine is a partial opioid agonist that causes less addiction and dependence than methadone and other full agonists.(1) Varenicline, a smoking cessation treatment, is a partial agonist at a specific subtype of nicotinic receptors (α4ß2).(2) In both cases, the partial agonism reduces craving, while the partial antagonism blocks the effect of additional doses of heroin or nicotine. In other words, the heroin or nicotine addict does not get the same “buzz” from the fix or cigarette, which reduces the reinforcement that contributes to addiction.

Inverse agonists
The traditional view essentially regards receptors as inactive until the agonist binds. The binding “switches on” the pathways inside the cell that lead to the biological action: the muscle contracting, for example. Think about a car ignition. The agonist is the key, the ignition lock the receptor, the engine the intracellular pathways and the car's motion the biological action. However, many receptors show spontaneous (“constitutive”) activity that keeps the cell's engine ticking over, even when there is no key in the ignition.
So how does the receptor keep the intracellular pathways ticking over? Essentially, the receptor has two shapes: one is active, the other inactive. The receptor oscillates between the active and inactive shapes. The receptor's shape - called its conformation - changes as it moves from being on to off and then back again.
Agonists bind to and stabilise the active conformation. Therefore, the receptor remains switched on for longer. Many so-called “antagonists” bind to and stabilise the inactive conformation. As a result, the receptor remains switched off for longer. In other words, they are not really antagonists at all. They bind and activate the receptor, but produce the opposite effect to the natural ligand. In other words, they are “inverse agonists”.
Think of a car travelling along a straight, empty motorway at 60 mph. The speed is equivalent to the constitutive activity. Agonists push down on the cell's “gas pedal”. Inverse agonists take foot off the cell's accelerator. Proper antagonists stop your foot getting to the pedal. In other words, full antagonists do not discriminate between the inactive and active conformations, but prevent ligands from binding.(1) Many current drugs marketed as antagonists are inverse agonists. In one study of 322 antagonists at 73 receptors, 85% acted as inverse agonists. Only 15% did not alter the receptor's constitutive activity (ie, were full “proper” antagonists).
Pharmaceutical companies are currently developing inverse agonists for numerous indications. For instance, the cannabinoid CB1 receptor is currently the subject of intense research interest. CB1 receptors bind a group of endogenous ligands called endocannabinoids, which includes anandamide and
2-arachidonoyl-glycerol. Antagonists and inverse agonists of the CB1 receptor could be valuable in obesity, osteoporosis, nicotine addiction and some mental illnesses. Indeed, the antiobesity drug rimonabant is an inverse agonist of CB1 receptors.(3)
However, a ligand's effect can be even more subtle than a “simple” inverse agonist. For example, whether a drug is a positive or inverse agonist can depend on the intracellular pathway that converts the binding of a drug or neurotransmitter to the receptor and the biological effect. Some hormones - such as vasopressin and oxytocin - are positive agonists for some pathways and inverse agonists in others.(4)
Indeed, a single receptor can engage two or more independent intracellular signalling routes. Cyclic adenosine monophosphate (cAMP) and the mitogen-activated protein kinase (MAPK) pathway are two examples of intracellular signalling networks. Propranolol is an inverse agonist for cAMP production and an agonist for the MAPK pathway.(5) Some serotonergic drugs produce hallucinations, which may arise from a differential response on signalling cascades.(1)
The classic theory also assumes that receptors are single entities - monomers - that act alone. However, in some cases two or more receptors join together (dimerise) to exert their effect. A dimer's effect is not necessarily the sum of the monomers' activity. For example, adenosine A1 receptors join to adenosine A2A receptors to produce a molecular “switch”. Low adenosine concentrations act on the “switch” to inhibit the release of glutamate, the most abundant excitatory neurotransmitter. High adenosine levels stimulate the release of glutamate.(6)
Adenosine A2A receptors can also form dimers with dopamine D2 receptors. Agonists of A2A receptors seem to change the conformation of the D2 receptor, reducing dopaminergic activity. Therefore, A2A antagonists could enhance the action of dopamine, which may offer, for example, a new approach to treating Parkinson's disease.(7)

Allosteric modulators
The area that binds the ligand is, usually, only a small part of the entire receptor. Most agonists, inverse agonists and antagonists bind to the same site as the endogenous ligand. However, many receptors have more than one binding site. These additional (“allosteric”) sites allow other drugs and endogenous ligands to “fine tune” the receptor's response. Allosteric modulators are a rapidly growing group of drugs that bind to one of these other sites.
For example, GABA (gamma-aminobutyric acid), the main inhibitory transmitter in the brain, contributes to, interalia, sleeping, feeding, aggression, mood, pain and cardiovascular function. Drugs targeting GABA are hypnotics, sedatives, tranquillisers and anticonvulsants. In response to GABA's or an agonist's binding, the GABAA receptor opens a channel that allows chloride into the cell. The GABAA receptor also contains other binding sites, including those for benzodiazepines, neuroactive steroids and barbiturates. Benzodiazepines are so-called “positive allosteric modulators”. In other words, benzodiazepines augment the endogenous ligand's effects. More specifically, benzodiazepines increase the frequency at which the chloride channel opens when GABA binds.(8)
As mentioned above, drugs acting on CB1 have considerable therapeutic potential. Currently, drugs targeting CB1 receptors also bind to other receptors - they're pharmacologically dirty. However, CB1 receptors express an allosteric site, discrete from the site that binds endocannabinoids. So targeting the allosteric site may offer greater specificity compared with conventional agonists.(3)
Furthermore, in some conditions increased endocannabinoid production may be a protective response. Potentially, allosteric modulators could enhance this protective effect without producing unwanted psychotropic effects. The allosteric modulator would be inactive at receptors that had not bound the endocannabinoid.(3)
Allosteric modulation of a glutamate receptor is emerging as a possible target for age-related cognitive decline, one of the most pressing clinical problems given the rapidly aging population. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are present throughout the CNS and seem to be critical to synaptic plasticity (the formation of new nerves and connections) generally and long-term potentiation, the synaptic changes that contribute to learning and memory, in particular. Positive allosteric modulators of AMPA seem to protect nerves from damage (neuro-protective) and improve cognitive function.(9)

Revolution is an overused word. Today, almost every new formulation, me-too or minor advance in theory seems to become hyped-up as a revolution. The change in thinking about receptor action is a true revolution; a profound shift in the way that pharmacologists view drug action. It is more than an academic issue - as we've seen the ideas are set to lead to more effective and better tolerated drug for numerous diseases.


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