Posted by Shawn. T. on July 29, 2002, at 3:31:34
Actions on dopamine receptors are unnecessary for the treatment of schizophrenia or bipolar disorder. The problem is actually a dysregulation of dopamine and glutamatergic transmission by serotonin 5-HT2 receptors (note that I finally discovered that human 5-HT2b receptors are not even located in the brain).
D2 dopamine receptor antagonism results in side effects that are unnecessary. For a rational description of schizophrenia, seehttp://biopsychiatry.com/schizoserotonin.htm
Aventis Pharmaceuticals will likely soon be releasing a potent new drug for schizophrenia, M,100,907. M,100,907 is a potent 5-HT2 antagonist. It has the same, perhaps even better, effects as current drugs available for schizophrenia treatment, only without the extrapyramidal side effects. Take for example Zyprexa (Olanzapine). Zyprexa exerts its effects on a very wide range of receptors. See http://www.gpcr.org/7tm/ligand/Organon/Tablig/LIG_C132539061.html
5-HT1a effects are within the range of weakly active, so that rules out 5-HT with regards to possible explanation of Zyprexa's efficacy. With regards to the dopamine receptors, the evidence seems to show that their activation is not necessary for the treatment of schizophrenia and leads to increased extrapyramidal side effects. See
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=1986311
With regards to NAa1, I am unaware of any reasoning that would support a role for it in schizophrenia. The effects on acetylcholine are unnecessary and produce side effects (memory impairment for example). Effects on histamine receptors, however, are transient and should disappear after a few weeks.
This would imply 5-HT2 antagonism as the mechanism of schizophrenia efficacy in Zyprexa.As mentioned in the study provided above, 5-HT2 antagonism is the key to treating schizophrenia. The extra effects on receptors unrelated to schizophrenia seen in current treatments are providing both the positive and negative effects of these drugs. M,100,907 would provide all of the positive effects of 5-HT2 antagonism and none of the negative effects caused by anticholinergic, antihistamine, and dopaminergic actions. I suggest that M,100,907, among other positive actions, helps to modulate dopamine release. It would prevent spikes in dopamine release in response to stressors or the introduction of drugs such as amphetamines. See
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=24612534
With regards to the negative and positive effects of schizophrenia and how M,100,907 affects these, see
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=7411933
and
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=11283291
Also examine the following study for an explanation of hallucinations in schizophrenic patients:
http://www4.infotrieve.com/search/databases/detailsNew.asp?artID=24922782Moreover, a 5-HT2 antagonist, Mirtazapine (Remeron) has been given regulatory approval in the United States. For this reason, I would suggest that a 5-HT2 antagonist would be a very tolerable agent to cure schizophrenia. M,100,907 has been shown to be more effective than both clozapine and haloperidol. Until M,100,907 is released, I would suggest that Remeron is currently the drug with the fewest side effects for schizophrenia treatment.
poster:Shawn. T.
thread:114125
URL: http://www.dr-bob.org/babble/20020725/msgs/114125.html