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

[Serhat]

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:

Hi Skorpio, I appreciate your detailed response and the points you've raised. I agree with you on the limitations of ChatGPT and the importance of relying on primary evidence and specialized databases.

I found your insights on the role of charge in membrane permeability to be quite enlightening. Your emphasis on the deterministic role of charge in a molecule's ability to cross lipid membranes is well-taken. However, I recently came across an article that adds a layer of complexity to this discussion.

The article, titled "Novel approaches to the design of bioavailable melanotropins" (link), delves into the intricacies of melanocortin receptors and their ligands. It discusses various strategies to improve the bioavailability of melanotropins, including cyclization and N-methylation. While the article is comprehensive, it does have some limitations that warrant discussion.

Firstly, the article seems to focus predominantly on the structural modifications of melanotropins to improve their bioavailability, but it doesn't sufficiently address the physiological transport mechanisms that would allow these modified peptides to cross the blood-brain barrier or other lipid membranes. This leaves a gap in our understanding of how these peptides interact with cellular transporters, which you rightly pointed out as being crucial for charged molecules.

Secondly, the article discusses the potential for biased signaling events on melanocortin receptors but doesn't provide empirical data to substantiate this claim. This raises questions about the physiological relevance of these signaling pathways and how they might interact with the charge and lipophilicity of the peptides.

Lastly, while the article does mention the potential for cyclotides and constrained tetrapeptides to improve oral bioavailability, it doesn't delve into the pharmacokinetics of these molecules. Understanding how these peptides are absorbed, distributed, metabolized, and excreted is crucial for assessing their potential as drug candidates.

Given these considerations, I would argue that while charge is undoubtedly a significant factor in membrane permeability, the interaction between peptides and cellular transporters, as well as the potential for alternative signaling pathways, adds a layer of complexity that shouldn't be overlooked.

I would be interested to hear your thoughts on these points.

 

[JohnBoy2000]

Scrolling through drug bank:

Afamelanotide: Uses, Interactions, Mechanism of Action | DrugBank Online

Afamelanotide is an injectable subcutaneous implant used to mitigate phototoxicity secondary to erythropoietic protoporphyria (EPP).

go.drugbank.com

PROPERTY	VALUE	PROBABILITY
Human Intestinal Absorption	+	0.9487
Blood Brain Barrier	-	0.9862
Caco-2 permeable	-	0.8823

What can we infer from this value?

It has a negative probability of crossing the BBB?

 

[JohnBoy2000]

The part I fail to understand;

If melanotan 1 does not cross the BBB,

https://www.ema.europa.eu/en/documents/product-information/scenesse-epar-product-information_en.pdf

Depression?

Tinnitus?

Last I checked they were mediated in the brain.

 

[JohnBoy2000]

Sci-Hub | Afamelanotide, an agonistic analog of α-melanocyte-stimulating hormone, in dermal phototoxicity of erythropoietic protoporphyria. Expert Opinion on Investigational Drugs, 19(12), 1591–1602 | 10.1517/13543784.2010.535515

As afamelanotide does not cross the blood--brain barrier to a significant extent in contrast to its cyclic analog, bremelanotide, no adverse effects resulting from signaling of brainlocated receptors have been recorded and the effects of systemically administered afamelanotide are predominantly restricted to the skin [62].

Afamelanotide (nM)
MC1R MC2R MC3R MC4R MC5R
0.085 >100 0.40 3.8 5.

 

[JohnBoy2000]

Seems like a good paper on mt1/2 and pt141.

Just haven't read it all:

Sci-Hub | Melanocortin peptide therapeutics: Historical milestones, clinical studies and commercialization | 10.1016/j.peptides.2005.01.029

It's been referenced as having specific info on BBB permeability re these chemicals, but I haven't found it therein yet.

 

[JohnBoy2000]

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 | 10.1517/21678707.2013.780969

]. When I first discovered the dramatic erectile response to an overdose of MTII, I also noted (as I lay in bed) that I was constantly vigorously stretching and yawning (acting like a rat). We can conclude, therefore, that MTII, unlike MTI, is able to cross the blood–brain barrier to mediate its actions in the brain as a neurohormone

Sci-Hub | Discovery that a melanocortin regulates sexual functions in male and female humans | 10.1016/j.peptides.2005.01.023

I'm beginnging to question the reliability of this conclusion.

Melanotan II in all likelihood must cross the blood brain barrier for its activity, which may explain the prolonged time to peak effect. Modi®cation of drug delivery may enhance acceptability for clinical use. The time at which nausea was ®rst reported, on average 168 min after injection, suggests that the gastrointestinal side effects are centrally mediated as well. The exact locus of action of Melanotan II remains unknown, but strong circumstantial evidence points to a central mechanism. Intracerebroventricular administration of Melanotan II in rats leads to erection and yawning, and no change in intracavernous pressure was observed after intracavernous injection (unpublished data). Melanotan I, a non-cyclic MCR agonist that does not cross the blood brain barrier, has no erectogenic activity. Further animal studies using selective melanocortin antagonists and agonists and receptor localization will be necessary to identify its pharmacological mechanism

Sci-Hub | Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II | 10.1038/sj.ijir.3900582

Just not seeing any definitive explanation for these BBB claims.

 

[JohnBoy2000]

https://escholarship.org/content/qt2gz9f9jk/qt2gz9f9jk.pdf

I can't copy/paste from this paper for some reason.

But it's short and end of page-1 claims it's lipophilicity responsible for BBB permeation in the case of mt2 versus mt1.


This seems like a good paper:

Sci-Hub | Novel approaches to the design of bioavailable melanotropins | 10.1080/17460441.2017.1351940

The MC3R and MC4R are mostly expressed in the central nervous system, and thus need to be modulated by peptides with the ability to penetrate the blood–brain barrier. The MC1R and MC5R are mainly expressed in the peripheral tissue, so that it is safer to modulate them with peptides that cannot get into the brain

● Cyclized melanotropin is a useful strategy for developing MCRs ligands due to their ability to penetrate the blood-brain-barrier. A promising way to improve oral bioavailability for cyclized peptide is to introduce N-methylation

Claiming the cyclic structure of mt2 causes great BBB permeability?

Compared to MT-I, which has limited ability to pass through the blood–brain barrier [25], cyclized peptides have their unique advantage of passing through the blood–brain barrier and exert direct actions in the central nervous system. In addition, cyclized peptides exhibit increased stability. The pro-erectile function of the cyclic peptide of MT-II was found to be mediated by MCRs in the brain and spinal cord [26].

Cyclized peptides have the ability to pass the blood–brain barrier, and thus are suitable for targeting MC3R and MC4R in the brain. Increasing lipophilicity of cyclized peptides with N-methylations can effectively improve selectivity and oral availability. Cyclotides have exceptional oral availability and are suitable to target MC1R and MC5R in peripheral tissues due to the inability to pass through the blood–brain barrier.

 

[AlsoTapered]

It's rather exciting to discover that some compounds that ignore the RO5 can enter the brain. In Skorpio's reference they often used the tactic of N-methylating the compounds but noted that selectivity and activity were frequently compromised.

BUT it would appear that active transport is required.

For me the key finding was that it was cyclic peptides that appear to cross more readily. So it could be that their is an active transport that isn't VERY selective. Possibly because the human body has never had to deal with cyclic peptides that are toxic?

The 3-phenyl-3-methylamino propanamide opioids I found papers on was shown to overlay part of a cyclic peptide that had opioid antagonist activity... but they did make one lacking the meta (2) phenol moiety on the B-ring which were shown to be agonists, I uploaded an image of the overlay.

So we may well begin to see CYCLIC peptide opioids. A few peptide opioids are recognized but they aren't very stable and have been shown to have low efficacy so research was halted.

For someone brought up being taught RO5, it suddenly increases the number of possible new medicines by orders of magnitude.

BUT I would like to know what that active transport is, or what THEY are,

Amazing - we didn't notice that a drug that had been in use for 2 decades entered the CNS... but of course, nobody was looking!

 

[JohnBoy2000]

This seems like a radioligand paper:

Sci-Hub | Fluorine-18-labeled [Nle4,d-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue | 10.1016/s0969-8051(96)00211-9

Therefore probably has more specific info on BBB crossing.

Will take a while to read through it.

Just to confirm: [Nle4,D-Phe7]-cx-MSH = NDP-α-MSH = melanotan 1

Can't quite determine if this is what I'm looking for.

Radioligand study of the hormone analogue, showing binding in brain tissue?

Which is claimed to be negligible?

If I could just find this for mt2/pt141, for comparison.