chemrox
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so basic it's almost lame
I want someone to point me in the right direction. I have a friend who has Parkinsonism symptoms but does not have Parkinson's according to his MD and
the lab said MD uses. I am asking which receptors would result in better dopamine activation without adrenal stimulation. There seem to be a series of
D2..D3..D4.. etc. If I wanted to find a way to relieve the shaking and confusion but without getting him "cranked" where would I start looking? Ideas
about possible probes? I want to preclude CNS stimulants and avoid opioids... He's been down the L-dopa routes (no joy.) He was a mentor of mine in
geophysics. His father suffered Parkinson's or the like several tens of decades back. I think the syndrome is inherited but what mechanism(s) might be
involved is still a mystery. Any speculation and/or knowledge will be gratefully received. I'm at the starting point with this. He responded well to
opioids except for the fatigue and de-motivation that came with them. Anyway, could you direct my reading? I need to learn about sub-receptors and
bindings in the D* realm. Is there a 'dopamine ligands for dummies' library?
"When you let the dumbasses vote you end up with populism followed by autocracy and getting back is a bitch." Plato (sort of)
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phlogiston
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This forum is a pretty poor source for medical advice. None of us are medical doctors as far as I know, and even if someone claims to be, how can you
be sure?
That being said, out of curiosity more than anything else, I was wandering what symptoms does your friend have that resemble parkinsons? And does he
have any other symptoms that are not typical of Parkinsons?
[Edited on 12-1-2016 by phlogiston]
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"If a rocket goes up, who cares where it comes down, that's not my concern said Wernher von Braun" - Tom Lehrer |
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ziqquratu
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I'm not entirely sure of how familiar you are with the biology, so forgive me if I'm telling you things you already know. My PhD involved some
dopaminergic medicinal chemistry (focused around the dopamine transporter, rather than the dopamine receptors), so I have some theoretical and
lab-based (but definitely not clinical!) background in the area. Also, this knowledge has laid unused for a few years now, so might be a little off or
out-of-date - but might give you something to help you in your searching. I would, however, note that your friend needs the opinion of a good
neurologist (ideally one who specialises in movement or neurodegenerative disorders), not some guy on a web forum!
PD is, essentially, defined by the loss of neurons within the substantia nigra, which is found in the midbrain and contains a large number of
dopaminergic neurons (about 75% of all CNS dopamine can be found in these neurons), most of which project to the striatum. Typical treatments involve
replacement of dopamine (essentially, treatment with l-DOPA, which is the biological precursor to dopamine); the use of dopamine agonists (compounds
which activate the receptors - typically ergots such as cabergoline or other drugs such as apomorphine); anticholinergics such as benztropine; or the
use of metabolic inhibitors (monoamine oxidase B inhibitors [MAOIs] such as selegiline or catechol O-methyl transferase [COMT] inhibitors such as
entacapone). There are a couple of other targets, but I can't quite recall them right now. Levodopa is typically highly effective, although the
effectiveness wanes with time until it reaches a point that the drug no longer works at all, or the side effects become intolerable (which is saying
something, since they can be bad enough from day one!). Dopamine agonists are generally associated with less severe motor impariment than levodopa,
although they can have greater side effects in other areas (particularly nausea and postural hypotension) and they generally won't work if levodopa
doesn't. Anticholinergics have largely been supplanted by the dopaminergics because of their side effects, but they can occasionally be useful when
patients can't tolerate or don't respond to those. The MAOIs and COMT inhibitors also work by increasing dopamine (by reducing metabolism), and have
levodopa-like side effects (although generally less severe) along with a few of their own (such as confusion).
So, basically, for PD itself, therapy largely consists of letting the surviving neurons control delivery of dopamine (by providing the precursor to
dopamine itself, or by preventing metabolism of the dopamine which is already there), or of replacing it entirely (agonists). Whilst the clinically
used ones tend to favour D1 and D2 receptors over other subtypes, all of the currently used dopaminergic agonists are pretty
dirty - meaning they hit multiple receptors (and not just dopaminergic receptors - serotonergic and adrenergic receptors are also affected to some
degree) with different degrees of potency. Dopamine replacement or metabolic inhibition is somewhat more targeted, since it relies on the fact that
surviving neurons will send their signals to the right places, but even then they have broader effects in the brain because dopamine isn't limited to
a single area (even though it is more concentrated to a smaller number of regions than most other neurotransmitters tend to be). The reason for this
is that all the receptors (the dopamine receptor subtypes, as well as the serotonin and noradrenaline receptors) are all sufficiently similar that
compounds which bind to one are entirely likely to bind to multiple others. Whilst there are compounds with high selectivity for at least some
receptor subtypes, which are used in lab studies which, for example, want to figure out the different roles of each receptor subtype, these are
typically very poor drugs - they may display excessive toxicity, poor solubility, low potency, and so on. Also, as a rule of thumb (with many
exceptions, of course), compounds which display the highest selectivity for one receptor over other related ones tend to be antagonists (blockers) of
the receptor, and treatment of PD involves dopamine receptor agonists.
As for side effects, it's a balancing act. There is some optimal range for dopamine concentration, and getting the brain to that point is the goal of
dopaminergic therapy; but if you go too far, you get stimulation or psychosis. The key is to find a dose which treats the disease without causing
those side effects - and for these types of therapies, that's difficult to do (and gets more difficult as the disease progresses and the drugs become
less effective - whilst, sadly, usually remaining entirely potent with respect to side effects).
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There are a number of syndromes which symptomatically resemble Parkinson's disease, but which arise through completely different mechanisms. The most
common "Parkinson's-like" disease is progressive supranuclear palsy - it presents quite similarly to PD, and is often misdiagnosed as such. Unlike PD,
which involves extensive cell death in a specific brain region, PSP is characterised by more widespread Interestingly, one of the most reliable ways
to differentiate the two (since there are no truly diagnostic tests for most of these types of neurodegenerative diseases - even brain imaging is
typically useless diagnostically, although it can be useful for monitoring an otherwise diagnosed condition in some cases) is that patients with PSP
will typically respond poorly to levodopa, although certain subtypes apparently do respond to some degree early on, making diagnosis even more
difficult! Also, PSP more often presents with visual symptoms (specifically, weakening of the eye muscles, which affects the ability to move the eyes
- particularly looking downwards, as I recall). The main treatments are physical therapy to help with speech and motor disabilities, along with drugs
to treat various other symptoms - there are no good options, sadly.
The other common alternative diagnosis is multiple system atrophy, which happens through a certain type of cell death followed by scarring in the
brain. I know little about this one, except to say that again diagnosis is difficult, response to dopaminergic medications is typically poor, and
treatment is pretty much entirely symptomatic.
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If you'd like to read up on some of the more obscure diagnoses which resemble PD, the easiest starting point would be Wikipedia. A decent entry-level review of the currently used drugs is attached below. As for an overview of the functions of the receptors, I'd
again suggest Wikipedia, which also gives links to pages on each of the subtypes (under the heading "Dopamine receptor subtypes", funnily enough), or an
undergraduate pharmacology textbook. I'd be happy try and help you with any questions you might think of from that, or to help you move forward from
this starting point. But again, having said that, I'm not a medical doctor, so I cannot offer clinical advice! Whilst I certainly approve of your
interest in understanding the situation better and your desire to help him, your friend needs to be receiving appropriate care from a suitably
specialised neurologist, and should not base any medical decisions on anything that's said here (or anything you get from Dr. Google).
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Dopamine agonists: their role in the treatment of Parkinson's disease
Brooks, D.J.
J Neurol Neurosurg Psychiatry 2000(68), 685-689 doi:10.1136/jnnp.68.6.685
Attachment: J Neurol Neurosurg Psychiatry-2000-BROOKS-685-9.pdf (184kB)
This file has been downloaded 562 times
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gregxy
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Deprenyl (selegline) a MAOI can be used to increase dopamine and may protect neurons as well.
Does he have "essential tremor" or Parkensons tremor? The Parkensons tremor is worse when the person is just sitting still.
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JJay
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Quote: Originally posted by ziqquratu  | I
There are a number of syndromes which symptomatically resemble Parkinson's disease, but which arise through completely different mechanisms.
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I absolutely agree. At a glance, it looks to me as though this may be what is happening here, but I would have to see test results to really
understand what is happening, and I don't claim to be able to do that at an MD level. Dopamine is a dangerous neurotransmitter to screw around with if
you don't know what you're doing.
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