<p>In fact, the two binding affinities of fentanyl and morphine to the mu opiate receptors are considered to be fairly similar. The reason the former is the more potent one has more to due with its higher <strong><a href="https://www.admescope.com/physicochemistry-and-binding/lipophilicity.html#:%7E:text=Lipophilicity%20refers%20to%20the%20tendency,logP%20or%20distribution%20coefficient%2C%20logD." rel="noreferrer">lipophilicity</a></strong> and therefore its better ability to cross the <a href="https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier" rel="noreferrer"><strong>blood brain barrier</strong></a>. In addition, their internal cellular signaling pathways differ. This is caused by the two compounds binding to slightly different amino acid residues in the opiate binding pocket of the mu receptor (Fig. 1) <a href="https://link.springer.com/article/10.1007/s00894-019-3999-2" rel="noreferrer">(Lipiński <em>et al</em>., 2019)</a>.</p>
<p>Another thing to consider, besides <strong><a href="https://www.bioagilytix.com/blog/2020/10/05/the-difference-between-pharmacokinetics-and-pharmacodynamics/" rel="noreferrer">pharmacodynamics</a></strong>, are the <strong><a href="https://www.bioagilytix.com/blog/2020/10/05/the-difference-between-pharmacokinetics-and-pharmacodynamics/" rel="noreferrer">pharmacokinetics</a></strong> of different compounds. For instance, methamphetamine is way more potent than amphetamine, which in turn is way more potent that its parent molecule PEA. This is because the methyl groups block MAO from degrading the compounds <a href="https://i.sstatic.net/ctTEd.png" rel="noreferrer">(Shulgin &amp; Shulgin, 1991)</a>. Pharmacokinetics may, or may not play a role in the morphine/fentanyl case as well.</p>
<p><sub><strong>References</strong><br />
<strong>-</strong> <a href="https://link.springer.com/article/10.1007/s00894-019-3999-2" rel="noreferrer">Lipiński <em>et al</em>., <em>J Molec Mod</em> (2019); <strong>25</strong>: 144</a><br />
<strong>-</strong> <a href="https://i.sstatic.net/ctTEd.png" rel="noreferrer">Shulgin &amp; Shulhin, <em>Pihkal</em>, Transform Press, 1991</a></sub></p>
<p><a href="https://i.sstatic.net/ctTEd.png" rel="noreferrer"><img src="https://i.sstatic.net/ctTEd.png" alt="pocket" /></a><br />
<sup>Fig. 1. Binding of fentanyl (a) and morphine (b) in the mu receptor binding pocket showing different amino acid residues in the receptor protein helices to be bonded causing differences in intracelllular signaling pathways to be activated. source: <a href="https://link.springer.com/article/10.1007/s00894-019-3999-2" rel="noreferrer">Lipiński <em>et al</em>. (2019)</a></sup></p>

CC BY-SA 4.0
2021-12-20T11:35:54.750Z
2021-12-20T15:07:13.167Z
2021-12-20T15:07:13.167Z
AliceD
<p>I'm rather new to neuropharmacology, and I am particularly interested in why some psychotropic medications are more potent than others despite being in the same category of one another, (<em>i.e.</em>: Oxymorphone, and Etorphine being both opioids) and acting as agonists at the same receptors. I am aware that binding affinities determine the potency and strength of a drug. <em>E.g.</em>:</p>
<p><a href="https://en.wikipedia.org/wiki/Morphine#:%7E:text=MOR%3ADOR%3AKOR-,Morphine,1.8%20nM,-90%20nM" rel="nofollow noreferrer">Morphine has an affinity of 1.8 nM (Ki)</a> on the MORs. Whereas <a href="https://en.wikipedia.org/wiki/Fentanyl#:%7E:text=MOR%3ADOR%3AKOR-,0.39%20nm,-%3E1%2C000%20nM" rel="nofollow noreferrer">Fentanyl has a binding affinity of 0.39 nM (Ki)</a> on the MORs. And so therefore, fentanyl requires a <a href="https://www.ncbi.nlm.nih.gov/books/NBK459275/#:%7E:text=fentanyl%20is%20a%20potent%20synthetic%20opioid%2C%20which%2C%20similar%20to%20morphine%2C%20produces%20analgesia%20but%20to%20a%20greater%20extent.%20this%20robust%20pharmacologic%20agent%20is%20typically%2050%20to%20100%20times%20more%20potent.%20a%20dose%20of%20only%20100%20micrograms%20can%20produce%20equivalent%20analgesia%20to%20approximately%2010%20mg%20of%20morphine." rel="nofollow noreferrer">far lower dose than morphine</a> for the patient receiving fentanyl to sustain adequate analgesia.</p>
<p>How are these two, totally structurally different opioids, able to agonise the same receptors, and how do the structures of them make one more potent than the other?
A similar question goes for the following Drugs:</p>
<p>Why are most Triazolobenzodiazepines, such as: <a href="https://en.wikipedia.org/wiki/Clonazolam#:%7E:text=while%20no%20dose%20of%20clonazolam%20is%20considered%20%22safe%22%20due%20to%20its%20lack%20of%20research%20and%20extreme%20potency%2C%20doses%20higher%20than%200.5%20mg%20can%20cause%20benzodiazepine%20overdose%20in%20some%20individuals" rel="nofollow noreferrer">Clonazolam</a>, <a href="https://en.wikipedia.org/wiki/Flunitrazolam#:%7E:text=the%20addition%20of%20the%20triazole%20ring%20to%20the%20scaffold%20increases%20potency%20significantly%2C%20this%20is%20evident%20as%20flunitrazolam%20is%20reported%20anecdotally%20to%20be%20active%20in%20the%20microgram%20level" rel="nofollow noreferrer">Flunitrazolam</a>, and <a href="https://www.drugs.com/dosage/triazolam.html#:%7E:text=Dose%20for%20Insomnia-,Initial%20dose%3A%200.25,reevaluation%20of%20the%20patient.,-Use%3A%20Short-term" rel="nofollow noreferrer">Triazolam</a> far more potent in their dose, and effects, then Benzodiazepines such as: <a href="https://www.medicines.org.uk/emc/product/1729/smpc#:%7E:text=usual%20dose%2010%20mg%2C%202%20%E2%80%93%203%20times%20a%20day%20and%20up%20to%2030%20mg%20daily%20in%20divided%20doses.%20for%20severe%20symptoms%2020%20mg%2C%202%20%E2%80%93%204%20times%20a%20day.%20maximun%20dose%20up%20to%20100%20mg%20daily%20in%20divided%20doses.%20adjusted%20on%20an%20individual%20basis.%20" rel="nofollow noreferrer">Chlordiazepoxide</a>, Nitrazepam, and <a href="https://www.medicines.org.uk/emc/product/4522/smpc#:%7E:text=Adults%3A-,Anxiety%20states%2C%20obsessive-compulsive,daily%20in%20divided%20doses.,-Muscle%20spasm%20of" rel="nofollow noreferrer">Diazepam</a>?</p>
<p>Why do small changes in the skeletal structure of psychoactive drugs have such a large impact on binding affinities?</p>

<neuroscience><psychopharmacology>
How does the chemical structure of a drug determine potency?
Firewind787
# How does the chemical structure of a drug determine potency?

(Asked by: username_0 on 2021-12-19)

I'm rather new to neuropharmacology, and I am particularly interested in why some psychotropic medications are more potent than others despite being in the same category of one another, (*i.e.*: Oxymorphone, and Etorphine being both opioids) and acting as agonists at the same receptors. I am aware that binding affinities determine the potency and strength of a drug. *E.g.*:

[Morphine has an affinity of 1.8 nM (Ki)](https://en.wikipedia.org/wiki/Morphine#:%7E:text=MOR%3ADOR%3AKOR-,Morphine,1.8%20nM,-90%20nM) on the MORs. Whereas [Fentanyl has a binding affinity of 0.39 nM (Ki)](https://en.wikipedia.org/wiki/Fentanyl#:%7E:text=MOR%3ADOR%3AKOR-,0.39%20nm,-%3E1%2C000%20nM) on the MORs. And so therefore, fentanyl requires a [far lower dose than morphine](https://www.ncbi.nlm.nih.gov/books/NBK459275/#:%7E:text=fentanyl%20is%20a%20potent%20synthetic%20opioid%2C%20which%2C%20similar%20to%20morphine%2C%20produces%20analgesia%20but%20to%20a%20greater%20extent.%20this%20robust%20pharmacologic%20agent%20is%20typically%2050%20to%20100%20times%20more%20potent.%20a%20dose%20of%20only%20100%20micrograms%20can%20produce%20equivalent%20analgesia%20to%20approximately%2010%20mg%20of%20morphine.) for the patient receiving fentanyl to sustain adequate analgesia.

How are these two, totally structurally different opioids, able to agonise the same receptors, and how do the structures of them make one more potent than the other?
A similar question goes for the following Drugs:

Why are most Triazolobenzodiazepines, such as: [Clonazolam](https://en.wikipedia.org/wiki/Clonazolam#:%7E:text=while%20no%20dose%20of%20clonazolam%20is%20considered%20%22safe%22%20due%20to%20its%20lack%20of%20research%20and%20extreme%20potency%2C%20doses%20higher%20than%200.5%20mg%20can%20cause%20benzodiazepine%20overdose%20in%20some%20individuals), [Flunitrazolam](https://en.wikipedia.org/wiki/Flunitrazolam#:%7E:text=the%20addition%20of%20the%20triazole%20ring%20to%20the%20scaffold%20increases%20potency%20significantly%2C%20this%20is%20evident%20as%20flunitrazolam%20is%20reported%20anecdotally%20to%20be%20active%20in%20the%20microgram%20level), and [Triazolam](https://www.drugs.com/dosage/triazolam.html#:%7E:text=Dose%20for%20Insomnia-,Initial%20dose%3A%200.25,reevaluation%20of%20the%20patient.,-Use%3A%20Short-term) far more potent in their dose, and effects, then Benzodiazepines such as: [Chlordiazepoxide](https://www.medicines.org.uk/emc/product/1729/smpc#:%7E:text=usual%20dose%2010%20mg%2C%202%20%E2%80%93%203%20times%20a%20day%20and%20up%20to%2030%20mg%20daily%20in%20divided%20doses.%20for%20severe%20symptoms%2020%20mg%2C%202%20%E2%80%93%204%20times%20a%20day.%20maximun%20dose%20up%20to%20100%20mg%20daily%20in%20divided%20doses.%20adjusted%20on%20an%20individual%20basis.%20), Nitrazepam, and [Diazepam](https://www.medicines.org.uk/emc/product/4522/smpc#:%7E:text=Adults%3A-,Anxiety%20states%2C%20obsessive-compulsive,daily%20in%20divided%20doses.,-Muscle%20spasm%20of)?

Why do small changes in the skeletal structure of psychoactive drugs have such a large impact on binding affinities?

**Tags:** neuroscience, psychopharmacology


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## 1 answers

### Answer by username_1 on 2021-12-20. Score: 6 | Accepted answer

In fact, the two binding affinities of fentanyl and morphine to the mu opiate receptors are considered to be fairly similar. The reason the former is the more potent one has more to due with its higher **[lipophilicity](https://www.admescope.com/physicochemistry-and-binding/lipophilicity.html#:%7E:text=Lipophilicity%20refers%20to%20the%20tendency,logP%20or%20distribution%20coefficient%2C%20logD.)** and therefore its better ability to cross the [**blood brain barrier**](https://en.wikipedia.org/wiki/Blood%E2%80%93brain_barrier). In addition, their internal cellular signaling pathways differ. This is caused by the two compounds binding to slightly different amino acid residues in the opiate binding pocket of the mu receptor (Fig. 1) [(Lipiński *et al*., 2019)](https://link.springer.com/article/10.1007/s00894-019-3999-2).

Another thing to consider, besides **[pharmacodynamics](https://www.bioagilytix.com/blog/2020/10/05/the-difference-between-pharmacokinetics-and-pharmacodynamics/)**, are the **[pharmacokinetics](https://www.bioagilytix.com/blog/2020/10/05/the-difference-between-pharmacokinetics-and-pharmacodynamics/)** of different compounds. For instance, methamphetamine is way more potent than amphetamine, which in turn is way more potent that its parent molecule PEA. This is because the methyl groups block MAO from degrading the compounds [(Shulgin & Shulgin, 1991)](https://i.sstatic.net/ctTEd.png). Pharmacokinetics may, or may not play a role in the morphine/fentanyl case as well.

**References**  
**-** [Lipiński *et al*., *J Molec Mod* (2019); **25**: 144](https://link.springer.com/article/10.1007/s00894-019-3999-2)  
**-** [Shulgin & Shulhin, *Pihkal*, Transform Press, 1991](https://i.sstatic.net/ctTEd.png)

[![pocket](https://i.sstatic.net/ctTEd.png)](https://i.sstatic.net/ctTEd.png)  
Fig. 1. Binding of fentanyl (a) and morphine (b) in the mu receptor binding pocket showing different amino acid residues in the receptor protein helices to be bonded causing differences in intracelllular signaling pathways to be activated. source: [Lipiński *et al*. (2019)](https://link.springer.com/article/10.1007/s00894-019-3999-2)


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