Corticotropin releasing hormone and modulators

[Refluxer]

While reading a review on purines as therapeutic agents I came across some pretty potent CRH receptor modulators. I'm not knowledgable in the biochemistry and function of CRH, but I figured some of you here might be. I'm interested in what function CRH has, what signalling pathways it effects, etc. From what I understood, CRH Inhibitors could really be a step forward in the field of anxiolytics and antidepressants.

Legraverend, M.; Grierson, D.S.; The Purines: Potent and versatile small molecule inhibitors and modulators of key biological targets, Bioorg. Med. Chem., 2006, 14, 3987-4006

 

[bfisher]

CRH Inh's have already been studied for a long time, n theres actually alot of info out there on them, even if your just using the web. i myself just educated myself recently like you. Pretty fuckin interesting shit.

 

[BilZ0r]

CRH as modulators of anxiety? While anythings possible, I would assume that agonists/positive CRH-receptor modulators, would give you an approximation of Cushing's syndrome, i.e. thin skin, face tummy, anxiety, panic, even psychosis, excess sweating and diabetes.

Antagonists/negative modulators would give you Addison's Disease; i.e. Chronic Adrenal Insufficiency i.e. fatigue, muscle weakness, nausea, depression, low blood sugar; and if I remember because of some whack thing to do with how ACTH is made from alpha-melanocyte stimulating hormone; you end up going black as well.

Sounds like a bad fucking scene to me.

 

[protovack]

As far as I know, CRH is a neuropeptide produced in the hypothalamus in response to stress. It travels down to the anterior pituitary where it stimulates Adrenocorticotropin hormone release. This stimulates the adrenal cortices to produce glucocorticoids such as cortisol. These then cause physiologic changes which adapt us to the stressor, i.e. protein catabolism, gluconeogenesis and a bunch of other stuff.

I remember seeing something about how CRH is not necessary for ACTH release...but is required for regulation of ACTH synthesis. I dunno, I'm not an endocrinologist

I'm not sure how CRH inhibition would help anxiety or depression. I really have no idea. You would need an intricate knowledge of the endocrine system to even take a stab at that one.

 

[Refluxer]

Perhaps there are subreceptors with differential functioning? I can't remember exactly what was behind the reasoning that these inhibitors might be developed as anxiolytics/antidepressants, but I think it had with genetically modified mice to do (lack or overexpression of the CRH receptor I suppose).

Bilzor's view doesn't sound too enticing. :D

 

[Blador]

Bilz0r is right. Only the hyperpigmentation of skin and mucous membranes would come with the CRH agonist, not the antagonist. ACTH and MSH come from the cleavage of the same polypeptide (pro-opiomelanocortin).

But that's just a model. There's certainly a lot more to it. Maybe receptors subtypes, but probably the goal isn't a major inhibition of cortisol production, only some regulation.
I too have read somewhere that inhibition of the HPA axis may be beneficial as an AD, as there's a theory in which depression is caused by degeneration of neurons (hippocampal?) provoked by chronic cortisol hyperstimulation, iirc...