Examining the literature on the potential for Afamelanotide (melanotan 1), to cross the Blood Brain Barrier:

[JohnBoy2000]

A lot of literature contends it doesn't, but I wanted to do a comprehensive'ish personal review on this.

As a preface, it's common knowledge that melanotan 2 and it's close analogue, Bremelanotide - DO readily cross the blood brain barrier.

However, due to the contention Afamelanotide is a bigger molecule, it apparently doesn't.

Afamelanotide:

Molecular Weight 1646.8 g/mol
a polypeptide comprising of 13 amino acids


Melanotan 2:

Molecular Weight 1024.2 g/mol
chain of 7 amino acids

.......

MT1 doesn't seem THAT much bigger though....?

 

[JohnBoy2000]

https://www.tandfonline.com/doi/full/10.1080/17512433.2021.1879638

Interesting point

The MC1R gene has a lot of polymorphisms, some of them associated with variation in pigmentation phenotypes within human populations [Citation52].

Mention of blood brain barrier crossing potential:

However, afamelanotide should not be confused with Melanotan-II (Ac-Nle-c[Asp, HisDPhe, Arg, Trp, Lys]-NH2) which is a smaller molecule than afamelanotide. Melanotan II is just as potent for skin pigmentation as afamelanotide and cheaper to manufacture, but can also cross the blood brain barrier and has more side effects including nausea and penile erections [Citation57,Citation58].

 

[JohnBoy2000]

What size molecules can cross the blood-brain barrier?

400–600 Da

Generally, only lipid soluble (lipophilic) molecules with a low molecular weight (under 400–600 Da) and of positive charge can cross the BBB

Possible strategies to cross the blood–brain barrier - Italian Journal of Pediatrics

The mucopolysaccharidoses (MPS) are a heterogeneous group of in-born metabolic conditions caused by genetic defects that result in the absence or severe deficiency of one of the lysosomal hydrolases responsible for the degradation of glycosaminoglycans (GAGs). Such enzyme deficiency causes...

ijponline.biomedcentral.com

......

According to Chat GPT:

Yes, afamelanotide is considered lipophilic

Afamelanotide is a peptide molecule, and its charge can depend on the pH of its environment. At physiological pH (around 7.4), afamelanotide is likely to be mostly in its zwitterionic form. A zwitterion is a molecule that contains both positive and negative charges within the same molecule, resulting in a net neutral charge.

 

[Skorpio]

ChatGPT is not a good source for information. Drugbank has info for logp of different compounds and afmelanotide is calculated to be negative (-1.4, -3.9, and -8.2 when calculated by different algorithns). This is of course less ideal than experimental data but leagues better than a large language model that just says things that sound right.

In general, peptides are going to be very un-lipophillic because they are both positively and negatively charged so they can never be uncharged. It's also big so the only way it would get into the brain is through active transport, which isn't super likely.

 

[JohnBoy2000]

ChatGPT is not a good source for information. Drugbank has info for logp of different compounds and afmelanotide is calculated to be negative (-1.4, -3.9, and -8.2 when calculated by different algorithns). This is of course less ideal than experimental data but leagues better than a large language model that just says things that sound right.

In general, peptides are going to be very un-lipophillic because they are both positively and negatively charged so they can never be uncharged. It's also big so the only way it would get into the brain is through active transport, which isn't super likely.

Would that size/length differential from mt2 (i.e. 0.6 kDa and 6 more amino acids in length), make it substantially bigger than mt2 - as far as the blood brain barrier is concerned?

MT2 is known to readily cross into the brain at a size which, to my untrained eye, doesn't seem too much smaller than mt1?

 

[Serhat]

Would that size/length differential from mt2 (i.e. 0.6 kDa and 6 more amino acids in length), make it substantially bigger than mt2 - as far as the blood brain barrier is concerned?

MT2 is known to readily cross into the brain at a size which, to my untrained eye, doesn't seem too much smaller than mt1?

The question of whether a peptide like MT1 would cross the blood-brain barrier (BBB) as readily as MT2 based solely on the difference in molecular weight (kDa) and length (number of amino acids) is complex and would likely depend on several factors, not just size or length. Generally speaking, peptides with a molecular weight of less than around 400-600 Da have a better chance of crossing the BBB, but this is far from the only consideration.

Here are some other key factors that could affect BBB permeability:

1. Lipophilicity: Lipid-soluble substances generally cross the BBB more easily than water-soluble substances.
2. Charge: The electrical charge on the molecule can affect its ability to cross the BBB. Neutral molecules generally cross more easily.
3. Transport Mechanisms: Some substances are actively transported across the BBB by specialized transport proteins.
4. Concentration Gradients: A high plasma concentration of a substance can drive it across the BBB to some extent.
5. Binding to Serum Proteins: Molecules that bind strongly to serum proteins may be less likely to cross the BBB.
6. Metabolic Stability: The peptide's resistance to enzymatic degradation can also affect how much of it ultimately crosses the BBB.

Given these complexities, it's difficult to say definitively whether the slight size/length difference between MT1 and MT2 would result in a significant difference in BBB permeability. The permeability would likely need to be assessed directly using experimental methods like in vivo pharmacokinetic studies.

 

[Skorpio]

Would that size/length differential from mt2 (i.e. 0.6 kDa and 6 more amino acids in length), make it substantially bigger than mt2 - as far as the blood brain barrier is concerned?

MT2 is known to readily cross into the brain at a size which, to my untrained eye, doesn't seem too much smaller than mt1?

What evidence do you have that it crosses the bbb?

 

[JohnBoy2000]

What evidence do you have that it crosses the bbb?

I thought it was one of those things about mt2 that was, as they say, "common knowledge"?

First thing I can pull up on google now:

Melanotan-II (MT-II) is a synthetic heptapeptide acting on both melanocortin-3 receptors (MC3R) and MC4R. Compared to α-MSH, MT-II has been described as 'a superpotent' melanocortin agonist with a long half-life in the plasma, and its cyclic structure confers better BBB permeability 25

https://onlinelibrary.wiley.com/doi/10.1111/jne.12454#:~:text=Melanotan%2DII%20(MT%2DII)%20is%20a%20synthetic%20heptapeptide,confers%20better%20BBB%20permeability%2025.

As I understood, it's the reason for side effects like sexual enhancement, nausea?

And a concurrent effect on oxytocin?

 

[JohnBoy2000]

 

[JohnBoy2000]

Tanning Injections: Risks, Side Effects, and Precautions

As more people are becoming aware of the potential dangers of tanning, they've started looking for alternatives, such as tanning injections. But are they safe?

www.healthline.com

Melanotan II binds with a wider range of receptors than melanotan I and has a shorter life in your body. It can also cross your blood-brain barrier, which can cause side effects like appetite loss, sexual dysfunction, and fatigue

 

[JohnBoy2000]

This is interesting also:

Drugs that stimulate oxytocin release promote social bonding in an animal model relevant to autism​

Females receiving the high dose of MTII and the low dose of BUS formed robust partner preferences. MTI did effect partner preference formation in this paradigm

Frontiers |

Frontiers Events is a rapidly growing calendar management system dedicated to the scheduling of academic events. This includes announcements and invitations, participant listings and search functionality, abstract handling and publication, related events and post-event exchanges. Whether an...

internal-www.frontiersin.org

 

[JohnBoy2000]

https://escholarship.org/content/qt2gz9f9jk/qt2gz9f9jk_noSplash_733feab97d2f5b6aa3f6492c4c174277.pdf?t=pdwtsk

So lypophilicity seems to be a determining factor according to this paper?

If I can find a good citation that melanotan 1 ISN'T lypophilic, I guess that would go some ways to indicating it may not cross the BBB?

 

[JohnBoy2000]

On melanotan 1, or Afamelanotide:

Animal studies have confirmed that that there is minimal and limited ability of afamelanotide to cross the blood-brain barrier

https://www.ema.europa.eu/en/documents/assessment-report/scenesse-epar-public-assessment-report_en.pdf

Apparently, the linear structure prevents afamelanotide from crossing the blood–brain barrier
after systemic application (23), in contrast to the closely related but cyclic bremelanotide (PT

Portico

access.portico.org

Apart from its binding to MC1R, afamelanotide binds weakly to MC3R and MC4R [50], which mainly are expressed in the gastrointestinal system and CNS, respectively. The inability of afamelanotide to penetrate the blood--brain barrier after systemic application prevents the activation of these receptors [51,52], and no anorexia or sexual stimulation is reported after application of therapeutic doses.

Sci-Hub | Afamelanotide for the treatment of erythropoietic protoporphyria. Expert Opinion on Orphan Drugs, 1(4), 341–349 | 10.1517/21678707.2013.780969

 

[JohnBoy2000]

There seems to be an allusion that the cyclic structure of mt2, facilitates its permeation of the BBB;

In contrast to the linear nature of mt1.

https://www.tandfonline.com/doi/abs/10.1080/17460441.2017.1351940

 

[Serhat]

https://escholarship.org/content/qt2gz9f9jk/qt2gz9f9jk_noSplash_733feab97d2f5b6aa3f6492c4c174277.pdf?t=pdwtsk

So lypophilicity seems to be a determining factor according to this paper?

If I can find a good citation that melanotan 1 ISN'T lypophilic, I guess that would go some ways to indicating it may not cross the BBB?

The concept of lipophilicity (or lipophilic nature) is indeed an important factor when considering the ability of a substance to cross the blood-brain barrier (BBB). The BBB is a highly selective semipermeable membrane that separates the circulating blood from the brain and extracellular fluid in the central nervous system. Lipophilic substances are more likely to pass through the BBB because the barrier is primarily made up of lipid layers.

Melanotan 1 and Lipophilicity​

If you can find a credible citation stating that Melanotan 1 is not lipophilic, it would indeed suggest that the compound is less likely to cross the BBB. However, it's important to note that lipophilicity is not the only factor that determines BBB permeability. Other factors include:

1. Molecular Size: Smaller molecules are generally more likely to cross the BBB.
2. Charge: Neutral molecules cross more easily than charged molecules.
3. Protein Binding: Some substances can cross the BBB when bound to a transport protein.
4. Concentration Gradient: A higher concentration of the substance in the blood can sometimes drive it across the BBB.

Verifying Claims​

To make a strong argument, you would ideally want to find peer-reviewed scientific papers or reviews that specifically discuss the lipophilicity of Melanotan 1 and its ability (or inability) to cross the BBB.

Would you like me to search for scientific papers or articles that discuss the lipophilicity of Melanotan 1?

 

[JohnBoy2000]

The concept of lipophilicity (or lipophilic nature) is indeed an important factor when considering the ability of a substance to cross the blood-brain barrier (BBB). The BBB is a highly selective semipermeable membrane that separates the circulating blood from the brain and extracellular fluid in the central nervous system. Lipophilic substances are more likely to pass through the BBB because the barrier is primarily made up of lipid layers.

Melanotan 1 and Lipophilicity​

If you can find a credible citation stating that Melanotan 1 is not lipophilic, it would indeed suggest that the compound is less likely to cross the BBB. However, it's important to note that lipophilicity is not the only factor that determines BBB permeability. Other factors include:

1. Molecular Size: Smaller molecules are generally more likely to cross the BBB.
2. Charge: Neutral molecules cross more easily than charged molecules.
3. Protein Binding: Some substances can cross the BBB when bound to a transport protein.
4. Concentration Gradient: A higher concentration of the substance in the blood can sometimes drive it across the BBB.

Verifying Claims​

To make a strong argument, you would ideally want to find peer-reviewed scientific papers or reviews that specifically discuss the lipophilicity of Melanotan 1 and its ability (or inability) to cross the BBB.

Would you like me to search for scientific papers or articles that discuss the lipophilicity of Melanotan 1?

Would you like me to search for scientific papers or articles that discuss the lipophilicity of Melanotan 1?

Yes please!!

There's one quotation linked above that indicates in animal models, mt1 doesn't cross the BBB "to any appreciable extent".

But if you're in a position to search through papers re lipophilicity?

That would be a tremendous help!

 

[Serhat]

Yes please!!

There's one quotation linked above that indicates in animal models, mt1 doesn't cross the BBB "to any appreciable extent".

But if you're in a position to search through papers re lipophilicity?

That would be a tremendous help!

I found some articles that might be relevant to your interest in Melanotan 1 and its potential to cross the blood-brain barrier:

1. Novel approaches to the design of bioavailable melanocortins: This article discusses the design of bioavailable melanocortins, which could include Melanotan 1.
2. Effect of Melanotan-II on Brain Fos Immunoreactivity and Oxytocin Neuronal Activity: While this article focuses on Melanotan-II, it might provide some insights into the melanocortin system and its effects on the brain.
3. Examining the literature on the potential for Afamelanotide (Melanotan 1) to cross the blood-brain barrier: This forum post discusses the potential of Melanotan 1 to cross the blood-brain barrier, citing various studies.
4. Melanocortinergic Activation by Melanotan II Inhibits Feeding: Another article on Melanotan II, but it discusses its effects on feeding behavior, which could be related to its ability to cross the BBB.

Unfortunately, I did not find any papers specifically addressing this topic. However, I did find some more articles that discuss factors influencing the blood-brain barrier permeability and the role of lipophilicity:

1. Neuropsychiatric Consequences of Lipophilic Beta-Blockers: Discusses how most beta-blockers are lipophilic and can cross the blood-brain barrier, leading to neuropsychiatric side effects.
2. Factors influencing the blood-brain barrier permeability: Provides an overview of the factors that influence the integrity of the blood-brain barrier.
3. Lipophilicity, hydrophilicity, and the central nervous system side effects: Discusses how crossing the blood-brain barrier is not necessarily synonymous with causing central nervous system effects.
4. Lipophilicity and its relationship with passive drug permeation: Discusses lipophilicity indices and their capacity to predict passive drug permeation across biological membranes like the blood-brain barrier.
5. The blood-brain barrier: structure, regulation, and drug delivery: Discusses the structure and function of the blood-brain barrier and its role in drug delivery.

While these articles don't specifically address Melanotan 1, they do provide valuable information on the factors that influence a substance's ability to cross the BBB, including lipophilicity.

 

[Serhat]

ChatGPT is not a good source for information. Drugbank has info for logp of different compounds and afmelanotide is calculated to be negative (-1.4, -3.9, and -8.2 when calculated by different algorithns). This is of course less ideal than experimental data but leagues better than a large language model that just says things that sound right.

In general, peptides are going to be very un-lipophillic because they are both positively and negatively charged so they can never be uncharged. It's also big so the only way it would get into the brain is through active transport, which isn't super likely.

Hey, thanks for sharing your thoughts. I get what you're saying about ChatGPT not being as specialized as Drugbank for stuff like LogP values. But let's be real, ChatGPT isn't trying to replace scientific databases. It's more like a jack-of-all-trades that can give you a good starting point on a bunch of topics. And it usually nudges you to double-check the facts, especially for science-y stuff.

About those LogP values for afmelanotide, you mentioned they vary depending on the algorithm, right? That kinda shows that even specialized tools like Drugbank aren't perfect and should be cross-checked too.

Now, about peptides being un-lipophilic yeah, I get that they're usually charged and all. But saying they're "always" like that is a bit of a stretch. There are exceptions, and a lot of things can affect how lipophilic a compound is, not just its charge.

And about peptides not getting into the brain easily sure, it's not super common, but it's not impossible either. There are active transport mechanisms that can make it happen. Saying it's "not super likely" without backing it up feels a bit like a jump to conclusions.

So yeah, while you've got some solid points, I think there's room for a more nuanced chat about this.

 

[AlsoTapered]

https://pubs.acs.org/doi/10.1021/bk-2022-1417.ch001

Nice reference that discusses active transport through various membranes.

From what I gather, this is a rather new field because so many proposals for calculations are included but not are very accurate).

One of the authors includes his (AOL!) E-mail address while the other it somewhat more reticent what with him being a Merck employee.

So go ask the expert. I have done so on a multitude of occasions and NOBODY had simply not replied. But then, I HAD read their paper and WAS asking an intelligent, informed question. Quite often they would be honest and say 'we don't know' or 'we hadn't thought of that' but ask a dumb question or swamp them and you WILL be blocked.

Don't forget - these people rightfully expect you to have read and understood their (years) of work.

 

[Skorpio]

So yeah, while you've got some solid points, I think there's room for a more nuanced chat about this.

ChatGPT is good for a bunch of things. It can rephrase writing and it is good at defining syntax for computer languages, but it is not reliable with facts. If you search journal articles, it will rework your question into paper titles, with DOIs which direct to random papers, as it knows the format of a paper reference and the makeup of a DOI. If you ask it to work through algebra, it will make mistakes and include things form outside the problem. If you ask it pharmacology questions, it will answer in a way that looks accurate, but the definate values and statements are not based in reality.

The different logPs from drugbank are due to differences in algorithms used. They are still computing the same input data. Their spread is instrument error, not a random number.

If something has a charge, it isn't crossing a lipid membrane, unless it is functioning like a detergant (and detergants at their critical micelle concentration would be lethal because of their dissolution of membranes). Lipophilicity can be altered by the balance of polar and nonpolar constituents of a molecule, but a charge is going to be a stronger force than anyother features of a molecule. If a peptide is charged, it is only going to be taken up by transporters (which I believe I stated in my original post).

Also if you've got a single paper with primary evidence, that is enough for me with regards to the brain penetration of afamelanotide. One of the links was to this thread.

The paper below talks about how melanotan I analogs were developed to provide blood brain barrier penetration.
Novel approaches to the design of bioavailable melanocortins: