[CH] capsaicin antagonists

Jack and Toni (jtblackford@intrepid.net)
Thu, 26 Sep 2002 19:58:50 -0400 

I went to a seminar today on resiniferatoxin, a capsaicin analouge from a 
cactus in Moroco, its 10,000 times as potent as capsaicin at blocking pain 
and is in trials currently for bladder problems, hopefully this cousin to 
capsaicin will provide even greater potential for pain relief than 
capsaicin does. And, also in the seminar they talked about antagonists for 
capsaicin - thats right - they do have things out there that will block the 
heat! No more Hunan hand, no more burning naughty bits - but - as I asked 
them about this application they didnt think it would be worth the effort, 
wouldnt pay enough to pursue commercially, but hopefully someone will take 
up the cause, because I love chiles but hate the occasional burning of the 
naughty bits!! Pepper Jack

Below is an abstract for fun, dont ask me to explain anything below, but 
maybe we could get the editors of Chilehead magazine to get in touch with 
some of the NCI guys to do a blurb about it???


Mol Pharmacol 2002 Oct;62(4):947-56

High affinity antagonists of the vanilloid receptor.

  Wang Y, Szabo T, Welter JD, Toth A, Tran R,
Lee J, Kang SU, Suh YG, Blumberg PM, Lee J.

National Cancer Institute, Bethesda, Maryland.
The vanilloid receptor VR1 has attracted greatinterest as a sensory 
transducer for capsaicin, protons, and heat, and as atherapeutic target. 
Here we characterize two novel VR1 antagonists, 
KJM429[N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea] 
andJYL1421[N-(4-tert-butylbenzyl)-N'-[3-fluoro-4-(methylsulfonylamino)benzyl 
]thiourea], with enhanced activity compared with capsazepine on rat VR1 
expressed in Chinesehamster ovary (CHO) cells. JYL1421, the more potent of 
the two novelantagonists, inhibited [(3)H]resiniferatoxin binding to rVR1 
with anaffinity of 53.5 +/- 6.5 nM and antagonized capsaicin-inducedcalcium 
uptake with an EC(50) of 9.2 +/- 1.6 nM, reflecting 25- and 60-foldgreater 
potencies than capsazepine. Both JYL1421 and KJM429 antagonized RTXaswell 
as capsaicin and their mechanism was competitive. The responses to JYL1421 
and KJM429 differed for calcium uptakeby rVR1 induced by heat or pH. 
JYL1421 antagonized the response to both pH6.0and 5.5, whereas KJM429 
antagonized at pH 6.0but was an agonist at lower pH (<5.5). For heat, 
JYL1421 fully antagonizedand KJM429 partially antagonized. Capsazepine 
showed only weak antagonism for both pH and heat. Responses of rVR1 
todifferent activators could thus be differentially affected by 
differentligands. In cultured dorsal root ganglion neurons, JYL1421 and 
KJM429likewise behaved asantagonists for capsaicin, confirming that 
theantagonism is not limited to heterologous expression systems. 
Finally,JYL1421 and KJM429 had little or no effect on ATP-induced calcium 
uptake inCHO cells lacking rVR1, unlike capsazepine. We concludethat 
JYL1421 is a competitive antagonist of rVR1, blocking response to allthree 
of the agonists (capsaicin, heat, and protons) with enhanced 
potencyrelative to capsazepine.


Go Fishing with Jack on the Potomac River, MD, USA at:
http://www.geocities.com/yosemite/rapids/8155