New peripherally adminsterable neurotensin peptide agonist

[nuke]

New peripherally administerable neurotensin peptide agonist

Synthesis and biological effects of c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012), a new analogue of neurotensin that crosses the blood-brain barrier.

Bredeloux P, Cavelier F, Dubuc I, Vivet B, Costentin J, Martinez J.

CNRS FRE 2735, Unité de Neuropsychopharmacologie de la dépression, IFRMP 23, Faculté de Médecine et de Pharmacie, 22 Boulevard Gambetta, Rouen cedex, France.

The central administration of neurotensin (NT) or of its C-terminal hexapeptide fragment NT(8-13), produces strong analgesic effects in tests evaluating acute pain. The use of NT-derived peptides as pharmaceutical agents to relief severe pain in patients could be of great interest. Unfortunately, peptides do not readily penetrate the blood-brain barrier. We have observed that the cyclic NT(8-13) analogue, c(Lys-Lys-Pro-Tyr-Ile-Leu-Lys-Lys-Pro-Tyr-Ile-Leu) (JMV2012, compound 1), when peripherally administered to mice produced analgesic and hypothermic effects, suggesting the peptide penetrates the blood-brain barrier and functions effectively like a drug. Moreover, dimeric compounds show increased potency compared to their corresponding monomer. We present the synthesis of the cyclic dimer compound 1 (JMV2012). In mice, compound 1 induced a profound hypothermia and a potent analgesia, even when peripherally administered. Compound 1 appears to be an ideal lead compound for the development of bioactive NT analogues as novel analgesics drugs.

http://www.ncbi.nlm.nih.gov/pubmed/18321036

As you can see they provide for analgesic and antinociceptive effect; they're also supposed to induce activity that enhances cognition. Neurotensin receptors have been indicated in the development of various mental disorders including schizophrenia and depression.

 

[morphiquet]

cool, although i think that all of those peptide-drugs will be dead ends due to obvious reasons:
only administerable via i.v.
low stability in a biological system and
in most cases tiny or no penetration of the blood-brain-barrier

the future definitely lies in small-molecule ligands or gene therapies.

 

[nuke]

This one benetrates the BBB. Aside from that, oral delivery systems that allow for the adminstration of large molecules have been studied pretty extensively for the past decade and drugs already exist that allow for their usage in this fashion. Depending on how the peptides are made, they can have very long or short durations of action, similar to small molecule drugs. There are very easy trick to extend duration. For instance, CJC-1295, often talked about in the steroids forum, has a two week half life.

Aside from that, it's very fashionable and easy these day to make your own peptides on the cheap -- there's a huge market for peptide synthesis now.

 

[morphiquet]

well, that maleimidopropionic-group that anquors the peptide on plasma proteins to prevent its enzymatic destruction is really fascinating.

do you think this would also be applicable towards other peptides in general?
and what about the costs of adding this protecting group to your peptide of choice when using one of those peptide-synthesis services?
i could imagine that this would make your peptide much more expensive....

 

[nuke]

Yes, I can't see why not. 3-maleimidopropionic acid is expensive (~$300 gram), but probably less so for chemical manufacturers who buy it in bulk. Keep in mind these compounds are usually much more potent than small molecule agonists too, and much less likely to interact with other receptors (reducing the amount of potential side effects). If you have something active in the microgram range, 100mg of this substance probably represents a large number of doses.

This (old) patent details a very large number of synthetic terminal 3-maleimidopropionic acid analogues: http://www.freepatentsonline.com/6849714.html

I'm sure with time much cheaper and more efficient ways to sythesize these compounds will be established too. I would expect to see many more of these drugs entering clinical trials in the next ten years.

Not to mention all these drugs are currently outside of any nation's analogue laws.

 

[Riemann Zeta]

Certain peptidomimetic compounds could be really cool, having cognition enhancing, neurotrophic and neuroprotective effects. There is one that can be derived from the sequence of the vasoactive intestinal polypeptide (which sounds remarkably boring, but apparently can do some cool shit in the CNS) called NAP, which is active at microgram dose levels and can be administered intranasally, reaching effective concentrations in the brain. And, as nuke mentioned, it is way off the radar for governments to shitcan with their draconian analogue laws.

 

[morphiquet]

yea i also have many targets in mind that sound stylish when it comes to peptide-responsive receptors (besides nts1 and vip/vpac-receptors).