Discussion: Foundational Neuroscience
The agonist-to-antagonist spectrum of action of psychopharmacologic agents
Prior to explaining the agonist-to-antagonist spectrum of action of psychopharmacologic
agents, it is important to understand the meaning of receptors. Receptors are specific proteins,
situated either in cell membranes or, in some cases, in the cellular cytoplasm. For each type of
receptor, there is a specific group of drugs or endogenous substances (known as ligands) that are
capable of binding to the receptor, producing a pharmacological effect. Most receptors are
located on the cell surface (Mijares, Lebesgue, Wallukat & Hoebeke, 2018). However, some
drugs act on intracellular receptors; these include corticosteroids, which act on cytoplasmic
steroid receptors, and the thiazolidinedione’s (such as pioglitazone), which activate peroxisome
proliferator-activated receptor gamma (PPARy), a nuclear receptor involved in the expression of
genes involved in lipid metabolism and insulin sensitivity.
Agonist is a ligand that bind to a receptor and produce an appropriate response are called
agonists. For example, the catecholamine adrenaline is an agonist at β-adrenoceptors. When it
binds to β-adrenoceptors in the heart, it increases the heart rate. On the other hand, antagonists
are ligands that prevent an agonist from binding to a receptor and thus prevent its effects are
called antagonists. Antagonists do not themselves have any pharmacological actions mediated by
receptors (Mijares, Lebesgue, Wallukat & Hoebeke, 2018). For example, propranolol, a β-
adrenoceptors antagonist, binds to β-adrenoceptors in the heart and prevents catecholamine-
induced tachycardia (for example in response to exercise). However, in the absence of an agonist
propranolol has no effect via adrenoceptors.
A full agonist is one that is capable of producing a maximal response, when it binds to a
sufficient number of receptors. In contrast, a partial agonist cannot produce the maximal
response of which the tissue is capable, even when it binds to the same number of receptors as a
full agonist binds to when it produces a complete response (Ganellin et al., 2017). Since the
effects of a ligand are generally produced by concentrations of the ligand that are well below
those that would bind to all the receptors necessary to produce a complete response, this means
that above a certain level of binding, a partial agonist may bind to receptors without producing
any further increase in effect. However, in so doing, it may prevent the action of other agonists,
and may thus appear to be acting as an antagonist. It is this mixture of actions that is called
partial agonism. For example, oxprenolol, which is a β-adrenoceptor antagonist, is also a partial
agonist. Thus, it may have less of an effect in slowing the heart rate than adrenoceptor
antagonists that do not have partial agonist action (i.e. full antagonists); this partial agonism of β-
blockers is sometimes called “intrinsic sympathomimetic activity” (ISA) (Ganellin et al., 2017).
In the case of β-adrenoceptor antagonists, the amount of β-blockade produced by a given
dose of the β-blocker will vary according to how much endogenous sympathetic nervous system
activity there is: the more activity, the more β-blockade will result from the action of a partial
agonist. This is clearly seen in the actions of the β-adrenoceptor agonist/antagonist xamoterol.
Xamoterol acts as a β-adrenoceptor agonist in patients with mild heart failure, improving cardiac
contraction. However, it acts as a β-blocker in patients with even moderate heart failure,
worsening it. For this reason it has not proved useful in clinical practice.
Most receptors have subtypes, for which certain ligands have some degree of selectivity.
For example, there are two main subtypes of β-adrenoceptors, called β1 and β2, both of which can
respond to adrenaline. Some β-adrenoceptor antagonists act at both β1 and β2 subtypes, while
some are selective for one and other subtype. For example, propranolol is an antagonist at both
β1 and β2 receptors, while atenolol is relatively selective for β1 receptors. Note that selectivity of
this kind is only relative; while a drug such as atenolol acts primarily on β1 receptors, at high
enough concentrations it can also have effects on β2 receptors (Mijares, Lebesgue, Wallukat &
Hoebeke, 2018).
Comparative analysis of the actions of g couple proteins and ion gated channels
Ion gated channels are ion channels that can open in response to the binding of a ligand.
To form a channel, this type of cell-surface receptor has a membrane-spanning region with a
hydrophilic (water-loving) channel through the middle of it (Yudin & Rohacs, 2019). The
channel lets ions to cross the membrane without having to touch the hydrophobic core of
the?phospholipid bilayer. When a ligand binds to the extracellular region of the channel, the
protein’s structure changes in such a way that ions of a particular type can pass through. In some
cases, the reverse is actually true: the channel is usually open, and ligand binding causes it to
close. Changes in ion levels inside the cell can change the activity of other molecules, such as
ion-binding enzymes and voltage-sensitive channels, to produce a response.?Neurons, or nerve
cells, have ligand-gated channels that are bound by neurotransmitters (Yudin & Rohacs, 2019).
On the other hand, g couple proteins are a large family of cell surface receptors that share
a common structure and method of signaling. The members of the GPCR family all have seven
different protein segments that cross the membrane, and they transmit signals inside the cell
through a type of protein called a G protein. GPCRs are diverse and bind many different types of
ligands (Yudin & Rohacs, 2019). One particularly interesting class of GPCRs is the odorant
(scent) receptors. There are about?800800800?of them in humans, and each binds its own scent
molecule – such as a particular chemical in perfume, or a certain compound released by rotting
fish-causes a signal to be sent to the brain, making us smell a smell.
The role of epigenetics in pharmacologic action
Epigenetics refers to the study of changes that influence the phenotype without causing
alteration of the genotype. It involves changes in the properties of a cell that are inherited but do
not involve a change in DNA sequence (Burkhart, Sharma & Ahuja, 2018). Epigenetics impacts
many areas of biomedicine like developmental biology, somatic gene therapy, cloning and
genomic imprinting. It is now known that in addition to genetic defects, epigenetic defects can
also result in disease. The field of epigenetics is inspiring the discovery of new drugs, and is
gaining importance as part of toxicology testing during drug development. This review will focus
on epigenetic therapy, and the use of drugs to correct epigenetic defects.
With recent improvements in understanding of the actual function of the entire genome,
pharmacology has to modify itself further to think of tackling diseases not in the conventional
‘drug-receptor’ sense, but in a more ‘global-response’ sense. Drugs may not be designed to be as
exact to a particular ligand or specific to a particular gene or protein subtype, they may indeed
have to be able to be more broad-acting over a range of epigenetic large-scale events (Burkhart,
Sharma & Ahuja, 2018). These larger-scale epigenetic regulatory mechanisms may span more
than one gene or family of proteins, they may in fact regulate large groups of genes. Importantly,
the advantage to this approach is that often, the epigenetic variations can be the underlying cause
of a particular disease, and simply targeting one protein of the multiple pathways involved may
be futile. Diseases such as cancer often have many different mutation variations that are difficult
to detect, predict and effectively treat, leading too often to relapse.
Epigenetic therapy, the use of drugs to correct epigenetic defects, is a new and rapidly
developing area of pharmacology. Epigenetic therapy is a potentially very useful form of therapy
because epigenetic defects, when compared to genetic defects, are thought to be more easily
reversible with pharmacological intervention. In addition to holding promise as therapeutic
agents, epigenetic drugs may also be able to prevent disease. However, epigenetic therapy has its
limitations, such as the fact that both DNMT as well as HDAC inhibitors may activate oncogenes
due to lack of specificity, resulting in accelerated tumor progression. Moreover, epigenetic states,
once corrected, may revert to the original state because of the reversible nature of DNA
methylation patterns.
How the information impacts the way medications are prescribed to clients
Epigenetics deepens our understanding of the human genome, that is, the whole picture
of our DNA makeup and how genes can be altered or modified by other factors. The study of
epigenetics adds to our genetic knowledge of addiction and shows how drug and alcohol abuse
can affect changes in our brains. It is helping us to understand that addiction is not only a
sequence of genes that causes risk, but also a sequence of risk that could change the way our
genes are expressed (Burkhart, Sharma & Ahuja, 2018). Epigenetic change occurs regularly and
naturally and is affected by a number of factors like age, environment, lifestyle and the state of
the disease. Of particular interest is how the environment influences epigenetic changes.
Therefore, I will prescribe drugs with regard to age, lifestyle, and genetic composition. At the
same time, beyond the use of medicines, individuals may be able to exert direct control over their
epigenome simply by modifying their diet or exposure to certain chemicals.
References
Burkhart, R., Sharma, A. R., & Ahuja, N.?(2018).?Epigenetic pharmacology. In?Pancreatic
Cancer(pp. 1551-1575). Springer New York.?https://doi.org/10.1007/978-1-4939-7193-
0_69.
Ganellin, C. R., Bang-Andersen, B., Khalaf, Y. S., Tertiuk, W., Arrang, J. M., Garbarg, M. ... &
Schwartz, J. C. (2017). Imetit and N-methyl derivatives. The transition from potent
agonist to antagonist at histamine H3 receptors. 1.?Bioorganic & medicinal chemistry
letters,?2(10), 1231-1234. https://doi.org/10.1016/S0960-894X(00)80219-X
Mijares, A., Lebesgue, D., Wallukat, G., & Hoebeke, J. (2018). From agonist to antagonist: Fab
fragments of an agonist-like monoclonal anti-β2-adrenoceptor antibody behave as
antagonists.?Molecular pharmacology,?58(2), 373-379. ?DOI:
https://doi.org/10.1124/mol.58.2.373.
Yudin, Y., & Rohacs, T. (2019). The G protein‐biased agents PZM21 and TRV130 are partial
agonists of μ‐opioid receptor‐mediated signaling to ion channels.?British journal of
pharmacology, 6(3), 89-102. https://doi.org/10.1111/bph.14702.
Zimmer, L. (2016). Pharmacological agonists for more-targeted CNS radio-
pharmaceuticals.?Oncotarget,?7(49), 80111. DOI:?10.18632/oncotarget.13418
