# Interesting information on 5ht receptors



## eric (Jul 8, 1999)

Not lotronex, but on current drug research.FYIDrugs 2001;61(3):317-32 Related Articles, Books Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. De Ponti F, Tonini M. Department of Pharmacology, University of Bologna, Italy. deponti###biocfarm.unibo.it Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity. PMID: 11293643 [PubMed - indexed for MEDLINE] ------------------Moderator of the Cognitive Behavioral Therapy, Anxiety and Hypnotherapy forumI work with Mike and the IBS Audio Program. www.ibshealth.com www.ibsaudioprogram.com


----------



## Guest (Apr 11, 2001)

interesting information. is this info available anywhere is simple language?tom


----------



## Kathleen M. (Nov 16, 1999)

I did a quick translation, maybe this will help>Although the past few years have seen an exponential growth of compounds>of potential interest for the treatment of functional gastrointestinal (GI) tract>disorders, the gap that still exists between basic and clinical research is easily>noticed if one considers the relative paucity of drugs that have received>marketing authorisation for the treatment of irritable bowel syndrome (IBS).While were all excited about getting drugs to treat functional GI problems we donï¿½t know enough about them to get them to market.>Traditional efficacy outcomes in drug development for IBS include the ability>of the compound to affect GI tract motility (i.e. to exert a prokinetic or an>antispasmodic effect), which is thought to be of importance if a motor>disorder is the underlying pathophysiological mechanism. More recently,>altered visceral sensitivity to a distending stimulus has been suggested to be a>key pathophysiological feature, at least in some patients, and has become aWe used to look only for drugs that altered how fast or slow stuff moved through the gut, but now we are interested in blocking the pain.>target for therapeutic interventions. However, there is now growing consensus>that the primary outcome measure in the treatment of functional disorders are>those that reflect overall control of the patient's symptoms (pain, diarrhoea,>constipation) in everyday situations such as the clinical global improvementWhat the patients really want is stuff thatï¿½ll help them have a good quality of life.>scales. Although, in general, guidelines on the design of treatment trials for>functional GI tract disorders advise against subcategorisation of patients>according to the main symptom (because of symptom instability),>subcategorisation indeed makes sense especially in IBS (constipation- or>diarrhoea-predominant). Compounds with a specific indication for each>subpopulation of patients are now emerging. We used to lump all IBSers together as well IBS symptoms can change all the time, but now weï¿½ve rethought that approach and will look at drugs that target specific sub-populations of IBSers. Now that we did that we are actually getting some drugs to market.>The rationale for investigations on>serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on>the fact that serotonin, which may be released by enterochromaffin-like cells in>the GI tract as well as from other sources, has a number of well documented>motor effects on the GI tract and can produce hyperalgesia in several>experimental models. We found out that certain specific types of cells release serotonin and we found out that serotonin changes how fast stuff moves through the gut. Also in some experimental models upping the serotonin causes excessive pain.>Serotonin receptors belonging to the 5-HT3 and 5-HT4>subtype are the most extensively studied in gastroenterology, although hitherto>'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors,So far weï¿½ve been looking at the popular receptors (# 3 and # 4) but there are some other receptors out there that weï¿½ve been ignoring, but maybe we should be looking at those too.>are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently>approved for the treatment of diarrhoea-predominant IBS and is an example of>a compound that, at least theoretically, may act at multiple levels: by inhibiting>visceral sensitivity, by increasing compliance, and by inhibiting excitatory>5-HT3 receptors located on both ascending and descending neuronal>pathways involved in peristalsis. Of the stuff we found that interacted with the #3 serotonin receptors alosetron (lotronex) was approved for IBS-D. We think (at least in theory we do) that it could be acting on a bunch of things including blocking pain, and blocing the gutï¿½s accelerator pedal.>For this reason, 5-HT3 receptor antagonists>may slow transit, hence the specific indication of alosetron in>diarrhoea-predominant IBS. However, alosetron has been recently withdrawnSince blocking the #3 serotonin receptor can slow the gut down it was used for IBS-D until it was withdrawn from the market.>by the manufacturer because of safety concerns. Hypomotility remains an>attractive therapeutic target in IBS and the new generation of prokinetics>includes several partial agonists at the 5-HT4 receptor, such as tegaserod>(HTF-919) and prucalopride (R0-93877). Blocking got to fast worked, so we started looking at blocking go to slow and looked for things that would speed things up (prokinetics). We found a couple of things tegaserod (Zelmac) and prucalopride.>In addition, preliminary evidence>suggests that 5-HT4 receptors may also be involved in the modulation of>visceral sensitivity. We lucked out, they also block pain.>Second-generation 5-HT4 receptor agonists seem to be>devoid of the QT-prolonging effects observed in some clinical circumstances>with cisapride and may be more active at the colonic level. Some of the older drugs that did this mucked up peopleï¿½s heart rhythms , but the new drugs donï¿½t do that and seem to work more on the colon than the stomach.>Piboserod>(SB-207266A) is a 5-HT4 receptor antagonist under development for the>treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and>5-HT(1B/D) receptor subtypes stems from the observation that the former>receptors mediate smooth muscle relaxation (at least in the human colon),>whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract>motility and visceral sensitivity.Piboserod activates the #4 serotonin receptor and that will slow down the gut and we are going to see if helps IBS-Ders.Now back to the unpopular receptors.Mucking with the #7 serotonin receptor looks like it might relax the smooth muscles of the colon (or at least in humans)Blocking the #1B/D serotonin receptor effects motility and pain.------------------I have no financial, academic, or any other stake in any commercial 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


----------



## Kerri (Oct 1, 1999)

Kmottus, Thank you for the explanation of the article that Eric posted. I have one question. One area saidiboserod activates the #4 serotonin receptor and that will slow down the gut and we are going to see if helps IBS-Ders.I am confused by this as all of the 5-HT4 stuff that is being developed is for C. Wouldn't that mean that 5-HT4 receptors would speed up the gut to help with C? Kerri


----------



## Kathleen M. (Nov 16, 1999)

There are agonists and antagonists. One blocks the receptor so nothing happens the other binds the receptor and activates it thus making something happen.K.------------------I have no financial, academic, or any other stake in any commercial 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


----------



## Guest (Apr 12, 2001)

thanks for the plain talk, k. I was being facetious earleir but do think it would help all if there were a simple explanation somewhere - media and medical news information sources seem to be behind the 8 ball at the moment and i'm sure doctors are experiencing problems keeping things straight. basic sources don't seem to be aware of cutting edge info at the monent and I think a lot of people are confused.tom


----------



## Kathleen M. (Nov 16, 1999)

There usually is a fairly substantial lag time between when stuff appears in the medical literature in science-babble and when (and often if) it gets published in english.Doctors should be fluent in science-babble, although sometimes some flavors of science-babble are hard to understand unless you happen to be in that specific field.I think the main problem with doctors is not that they cannot understand the scientific literature, but the daunting task of keeping current with it given the vast amount of articles published every year. Particularly for the generalist. Usually the more specialized you are the easier it is to keep up with the literature, but OTOH they generally only know what is current in their narrow field.K.------------------I have no financial, academic, or any other stake in any commercial 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


----------

