Posted by Shawn. T. on July 3, 2005, at 23:07:47
In reply to How do these drugs work? In phase III trials, posted by ravenstorm on July 3, 2005, at 17:56:33
Substance P has a low affinity (which results in low potency) for NK2 receptors. Neurokinin A is the high affinity agonist for NK2 receptors that is naturally present in the body. So NK2 antagonists like saredutant primarily interfere with the effects of neurokinin A. Substance P and neurokinin A are called tachykinins; this group also includes neurokinin B, neuropeptide K, and neuropeptide gamma. They're all likely to have some affinity for NK2 receptors.
One of the key substances involved in anxiety and depression is CRF. This peptide acts to modulate physiological processes in the brain and body during stressful situations. Part of this role involves increasing the release of certain neurotransmitters in various regions of the brain. Researchers have found that NK2 receptor antagonists such as saredutant can reduce the CRF-induced release of norepinephrine in the prefrontal cortex and acetylcholine in the hippocampus (see the two links below). Thus, they believe that some of the effects of CRF on neurotransmitter release may involve a CRF-induced increase in neurokinin A. These researchers have also found that NK2 antagonists increase CREB levels in the hippocampus after long term treatment; this is an effect shared by most antidepressant drugs. In addition, they found that NK2 antagonists reduce stress-induced substance P release.
http://jpet.aspetjournals.org/cgi/content/full/299/2/449
Also, NK2 antagonists may inhibit the HPA axis:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9663462
The take home message here is that the mechanism of action of saredutant (SR 48968) suggests that it is perhaps the most promising drug in phase II or phase III clinical trials for anxiety and depression. The drug is currently in phase III in the US, and Sanofi-Synthelabo claims that the phase IIb results were "very promising."
I'm not sure about the role that beta-3-adrenoceptors might play in depression. All I can tell you is that they are activated by norepinephrine.
Shawn
poster:Shawn. T.
thread:523047
URL: http://www.dr-bob.org/babble/20050702/msgs/523162.html