The future looks bright for people with vasculogenic erectile dysfunction

The role of Adenosine in erections: A detailed examination with focus on CF602 - a promising new ED drug candidate

First, let's do a TL;DR, and then I will give all the details for readers who want to know more: 

TL;DR: How CF602 Helps with Erectile Dysfunction

Erectile dysfunction (ED) is a common problem where a man has difficulty getting or keeping an erection. One key player in this process is a substance called adenosine, which helps increase blood flow to the penis, making it easier to get an erection.

What is CF602?

CF602 is a new drug being developed to treat ED. It works by enhancing the effects of adenosine in the body. Think of adenosine as a key that unlocks a door, allowing blood to flow into the penis. CF602 makes this key work better, leading to improved erections.

How Does It Work?

1. Adenosine and Erections:

   • Adenosine helps relax the smooth muscles in the penis, allowing more blood to flow in.
   • This increased blood flow is essential for achieving and maintaining an erection.

2. Role of A3 Adenosine Receptor (A3AR):

   • CF602 targets a specific receptor called A3AR. When adenosine binds to this receptor, it triggers a chain reaction that helps relax smooth muscles and improve blood flow.
   • By enhancing this binding, CF602 boosts the effects of adenosine, making erections easier to achieve.

Benefits of CF602

• Effective in Diabetic Rats: In studies with diabetic rats, a model often used for ED research, CF602 significantly improved erectile function.
• Versatile Administration: CF602 can be taken as a pill or applied directly to the skin, making it convenient.
• Long-lasting Effects: The improvements in erectile function were not just temporary; they lasted over time, suggesting that CF602 might provide lasting benefits.

Conclusion

CF602 is a promising new treatment for ED that works by enhancing the natural effects of adenosine, a substance that helps increase blood flow to the penis. This drug could offer a new option for men struggling with ED, especially those who haven't had success with existing treatments. 

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Ok, now that the TL;DR is out of the way, let's jump into the meat of the matter - the biochemistry of erections. I have written before about the anatomy of an erection, how PDE5-inhibitors work, etc. I will not rehash the biomechanics in this post, but focus specifically on the role of Adenosine. 

 

Erectile function is a complex physiological process involving a delicate interplay of neural, vascular, hormonal, and psychological factors. Among these, the role of adenosine, a ubiquitous nucleoside, has garnered significant interest in recent years due to its multifaceted involvement in various physiological processes (it's everywhere). This write-up looks at the intricate mechanisms by which adenosine influences erectile function, providing insights into its potential as a target for therapeutic intervention in erectile dysfunction (ED).

 

Adenosine and its Receptors

Adenosine exerts its effects through four known G-protein coupled receptors: A1, A2A, A2B, and A3. Each receptor subtype mediates distinct physiological responses in different tissues in the body. The A3 adenosine receptor (A3AR) is particularly noteworthy in the context of erectile function due to its unique expression pattern and the downstream signalling pathways it modulates:

 

Mechanisms of Adenosine in Erectile Physiology

Erection is fundamentally a haemodynamic event initiated by the relaxation of smooth muscle cells within the corpus cavernosum. This relaxation leads to an increase in blood inflow and engorgement of the penile tissue, which shuts off outflow though the veno-occlusive mechanism, which I have written of before.

Nitric oxide (NO) plays a pivotal role in this process by activating guanylate cyclase, which increases cyclic guanosine monophosphate (cGMP) levels, leading to smooth muscle relaxation. Adenosine contributes to this cascade by enhancing NO production through various pathways, notably by activating endothelial nitric oxide synthase (eNOS). 

 

The A3 Adenosine Receptor: A Novel Target

Recent advancements in ED treatment have shifted focus towards the A3AR, given its involvement in multiple beneficial physiological processes. Can-Fite BioPharma Ltd. has been at the forefront of this exploration with their development of CF602, a highly selective positive allosteric modulator (PAM) of A3AR. (A PAM is a substance that specifically targets and enhances the activity of a particular receptor in the body without directly activating it. This means it makes the receptor work better only when the natural substance (like adenosine) is present.)

 

CF602: A Promising Therapeutic Agent

CF602, formerly known as LUF6096, represents a novel class of ED drugs targeting A3AR. Unlike traditional treatments that primarily focus on PDE5 inhibition, CF602 enhances the NO-cGMP pathway through a distinct mechanism, potentially offering synergistic effects when used in combination with existing therapies.

1. Mechanism of Action:

   • CF602 amplifies the activation of A3AR, which in turn stimulates phospholipase C (PLC).
   • This activation leads to an increase in inositol triphosphate (IP3), promoting eNOS activation and subsequent NO production.
   • The resultant NO augments the cGMP pathway, facilitating smooth muscle relaxation and improved erectile function.

2. Anti-inflammatory and Cardioprotective Effects:

   • A3AR modulation by CF602 has shown anti-inflammatory properties, enhancing the anti-inflammatory effects of macrophages.
   • This dual functionality not only aids in treating ED but also offers cardioprotective and neuroprotective benefits, potentially addressing comorbid conditions often associated with ED.

3. Pre-clinical Efficacy and Safety:

   • In pre-clinical studies, CF602 has demonstrated the ability to restore vascular endothelial growth factor (VEGF) expression, possibly through the PI3K/Akt pathway. (Note: we know it works, but not how it works)
   • Its pharmacokinetic profile suggests excellent bioavailability, making it suitable for oral or topical administration. (Topical means you can make a salve to rub on, with some agent to improve skin permeability.)
   • Preliminary safety data from its predecessor, Piclidenoson, indicates a favourable safety profile, with common side effects being mild and related to adenosine receptor agonism. People with asthma might want to avoid it though, due to A3AR expression in lung tissue.

Long-Lasting Effects of CF602

A recent study conducted by Can-Fite BioPharma Ltd. explored the efficacy of CF602 in a diabetic rat model of ED, revealing promising long-lasting effects. This study utilised streptozotocin-induced diabetic rats screened for ED using the apomorphine test. The assessment involved measuring intracavernosal pressure (ICP) and mean arterial pressure (MAP) during electrostimulation of the cavernosal nerve. 

Link to study here: https://www.canfite.com/userfiles/banners/M69.pdf 

 

Key findings from the study include:

• Significant Improvement in Erectile Function:

  • A single dose of CF602, administered either topically or orally, resulted in a dose-dependent improvement in the ICP
    ratio, indicating enhanced erectile function without affecting systemic blood pressure.
  • This improvement was noted with both administration methods, showcasing the versatility of CF602.

• Sustained Physiological Benefits:

  • The study also observed a significant increase in the smooth muscle ratio, VEGF, and eNOS levels in treated rats, suggesting structural and functional improvements in penile tissue.
  • These findings imply that CF602 not only provides immediate relief but may also induce long-lasting beneficial changes in the erectile tissue.

Implications for Erectile Dysfunction Treatment

The exploration of A3AR modulation opens new avenues for ED treatment. CF602’s unique mechanism offers a promising alternative for patients who do not respond adequately to current therapies. Its ability to synergise with PDE5 inhibitors and NO precursors, coupled with its anti-inflammatory and cardioprotective properties, positions it as a versatile and potentially highly effective therapeutic option.

 

Conclusion

Adenosine, particularly through its action on A3AR, plays a central role in the regulation of erectile function. The development of CF602 could be an important advancement in ED treatment, by way of adenosine receptor modulation. As CF602 progresses through the clinical development pipeline, it holds the potential to revolutionise the treatment of vasculogenic erectile dysfunction since the effects appear long-lasting. It could potentially provide a cure, not just a treatment. 

 

Sadly, that pipeline is a slow process. It might be a decade before this is available. Myself, I don't have vasculogenic ED - my erections work well, once I get them. My own issue has always been my nerves whenever I am with a new partner, which has been detrimental to my life as a swinger. I need my wife to be my fluffer sometimes - or another lady I have good chemistry with since before. Despite not needing it, however, I want to try. I believe there is a chance that a bunch of enthusiasts from the PharmaPE subreddit might organise a CF602 group buy (custom synthesis by a research lab) - if you head over there and take a look, you might be able to snatch yourself a spot; not all who asked to be included have gone ahead and paid from what I understand. (Note: I would obviously never advise anyone to use an untested research chemical on their penis. If you do so, it's all on you.)

I hope you have enjoyed this write-up - and if you suffer from ED, I hope it gives you a little hope for the future of adenosine-receptor modulators. I happen to know there are other substances that have even more affinity for the specific receptor found in penile tissue, so these are exciting times to be alive. 

/Karl