# Effects of TAK-637, a neurokinin-1 receptor antagonist, on colonic function in vivo



## Jeffrey Roberts (Apr 15, 1987)

http://www.ncbi.nlm.nih.gov/entrez/query.f...&db=PubMed&list _uids=11454917&dopt=Abstract[/URL] Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivkano S, Nagaya H, Ikeura Y, Natsugari H, Inatomi N.Pharmaceutical Discovery Research Division and Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as *irritable bowel syndrome*.PMID: 11454917 [PubMed - indexed for MEDLINE][This message has been edited by Jeffrey Roberts (edited 09-10-2001).]


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## Jeffrey Roberts (Apr 15, 1987)

This study is essentially about a new class of drugs perhaps for IBS. However, the comparison to *Zofran* (ondansetron) seems encouraging.Another study about Ondansetron can be found here: http://www.ncbi.nlm.nih.gov/entrez/query.f...db=PubMed&list_ uids=8853764&dopt=Abstract[/URL][This message has been edited by Jeffrey Roberts (edited 09-10-2001).]


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## Jeffrey Roberts (Apr 15, 1987)

Here are a list of clinical studies for this NK-1 receptor antagonist that was mentioned in the above study. http://clinicaltrials.iupui.edu/trials/Irr...%20Syndrome.htm http://www.viahealth.org/via_news/news2000/july/tghibs.htm [This message has been edited by Jeffrey Roberts (edited 09-10-2001).]


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## Jeffrey Roberts (Apr 15, 1987)

NK-1 receptor agonist's are being marketed now for other illnesses. Namely migraines. The drug *Imitrex* is one NK-1 receptor agonist.Is anybody on this for migraines? Have you noticed if your IBS improves from it?[This message has been edited by Jeffrey Roberts (edited 09-10-2001).]


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## Kathleen M. (Nov 16, 1999)

I'll try to translate


> quote:Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear.


Substance P (abbreviated as SP for the rest of the paper) is an important chemical nerves use to talk to each other [pain is one of the things it is involved with] that has a number of roles in gut functions. However...we don't understand it.


> quote: In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils.


In this study we looked at the effect of SP in the function of the colon and the effect of TAK-637 [which has this really really obnoxious name when you describe exactly what it is and now you know why we call it TAK-637] which is something new that binds to the a particular receptor on nerve cells (NK1) and blocks what happens when it is activated. We did this in the colons of Mongolian gerbils.


> quote:SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output.


If we put SP and this compound that activates the NK1 receptor they poop more.


> quote:TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation.


 The drug TAK-637 blocked the extra pooping the gerbils do when you give them the above mentioned drug, so we increased poop production with a bunch of other things, and this drug didn't effect any of those. [this shows the action of the drug is specific...it doesn't slow down all the ways that increase poop, just a specific one]


> quote:Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg.


When the animals are stressed out they poop more [sound familiar--Your trapped in a car in a traffic jam and no bathroom is in sight







] and TAK-637 stopped that from happening at certain doses (and we know which ones







)


> quote:Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation.


We took some other drugs Zofran and Atropine (which is one of two drugs in Lomotil) and they also reduced the amount of poop the stressed gerbils produced.


> quote: TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels.


So we looked in the literature for all the ways you can increase poop output. For the one where we put stuff in their brains, it stopped it, but the amount of stress-related stuff in the blood was the same as without TAK-637


> quote: Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation.


Now what's really cool about Substance P in your head is you can eat really hot chili peppers and deplete all the SP in your head and not be able to get a head ache for awhile. We feed them red hot chili peppers, but that didn't effect the stress-stimulated poop-fest.


> quote: These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.


We think we know what pathways make you poop more when you are stressed. AND TAK-637 may (if man is like a gerbil) be useful for IBS.K.------------------I am a scientific researcher primarily in the area of the environment and the impact of environmental factors on human health, I have no ties to the pharmaceutical industry. I have no financial, academic, or any other stake in any commercial, natural, or any other product mentioned by me.My story and what worked for me in greatly easing my IBS: http://www.ibsgroup.org/ubb/Forum17/HTML/000015.html[This message has been edited by kmottus (edited 09-10-2001).]


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## Jennifer7 (Nov 13, 2000)

I think there was something on here a while back about several people in England being "cured" of IBS with Imitrex.


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## flux (Dec 13, 1998)

> quote:NK-1 receptor agonist's are being marketed now for other illnesses. Namely migraines. The drug Imitrex is one NK-1 receptor agonist.


Imitrex is *not* an NK-1 agonist. I don't know of any such agonists currently being marketed, but I didn't research this.


> quote:Is anybody on this for migraines? Have you noticed if your IBS improves from it?


Imitrex is a 5HT-1D agonist. At least one study found that it helps the stomach relax to distension and could be useful to treat gastric dysryhthymias.------------------I am not a doctor, nor do I work for profit in the medical/pharmacological field, but I have read scientific and medical texts, and have access to numerous sources of medical information that are not readily available to others. One should always consult a medical professional regarding advice received.[This message has been edited by flux (edited 09-10-2001).]


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