Macro-synergy: polypill w/ APIs @ doses singly NOEL @ target when ea. solo (theory)

[Nagelfar]

Why aren't simple medications for agonism/antagonism of the *highly variable* sub-type receptor classes (with regard to their affectations) in the monoamine system, biogenic amines, etc. singled out for just agonism or antagonism of one DA, 5-HT or NE receptor sub-type with no other appreciable affinity, and included together in one formulation with other chemicals which are exactly as selective, but for another site and agonism for some and antagonism for others? Wouldn't this be the most logical direct and intelligent/rational (and educational to academia + research of behavioral relationship to what brain function!) direction for anti-depressant "SSRI" type of drugs. Instead of 200mg of one compound that has fairly random affinity for a few different spots where the subjective good results are yielded in the over-all observation of how it suits depression?

Wouldn't putting, say, seven compounds at ultra low dose (the highest of which should start @ "NOEL = No Observed Effect Level, the highest dose known to show no effect"), for their subtle synergy in the bigger picture each with its own unique level of affinity to just one site, where it selectively activates it or blocks it from activation (specifically in the serotonin receptor sub-types where some are related to dysphoria and others with mood elevation)

Shouldn't this, or wouldn't this be the logical end point of rational drug design when it comes to straight-forward and pure desire for patient's welfare?

 

[Jabberwocky]

Why aren't simple medications for agonism/antagonism of the *highly variable* sub-type receptor classes (with regard to their affectations) in the monoamine system, biogenic amines, etc. singled out for just agonism or antagonism of one DA, 5-HT or NE receptor sub-type with no other appreciable affinity, and included together in one formulation with other chemicals which are exactly as selective, but for another site and agonism for some and antagonism for others? Wouldn't this be the most logical direct and intelligent/rational (and educational to academia + research of behavioral relationship to what brain function!) direction for anti-depressant "SSRI" type of drugs. Instead of 200mg of one compound that has fairly random affinity for a few different spots where the subjective good results are yielded in the over-all observation of how it suits depression?

Wouldn't putting, say, seven compounds at ultra low dose (the highest of which should start @ "NOEL = No Observed Effect Level, the highest dose known to show no effect"), for their subtle synergy in the bigger picture each with its own unique level of affinity to just one site, where it selectively activates it or blocks it from activation (specifically in the serotonin receptor sub-types where some are related to dysphoria and others with mood elevation)

Shouldn't this, or wouldn't this be the logical end point of rational drug design when it comes to straight-forward and pure desire for patient's welfare?

I don't know of ANY compounds that are ONLY active at a particular subreceptor of only 1 Type, and not active anywhere else. Can you identify some?

Even Baclofen which is highly selective to only GABAb -- also affects Voltage gated calcium channels[h=3][/h]

 

[serotonin2A]

For certain indications, drugs with a reasonable degree of selectivity are preferred. SSRIs are an example of drugs that were developed to selectively bind to one target. The problem is that it is not simple to develop drugs with selective binding profiles -- different monoamine receptors display a relatively high degree of homology.

For other indications, such as schizophrenia, hitting multiple targets can improve efficacy or reduce side-effects. The strategy you are proposing -- developing multiple selective drugs -- is a drug development nightmare.

Think about the following problems:
* Most new drugs fail to reach market. For a project that requires 2 or more new drugs to succeed, the odds of success are much much lower.
* You would have to run dose-finding studies to determine the optimal dose for each drug, and then you would have to run other studies to determine the optimal dose ratio. That is a lot of clinical trials!
* It is possible that there may not be one optimal dose ratio that works for all patients, which would derail the project.
* There may be complex PK interactions between the drugs. At the very least you would have to characterize the potential PK interactions. But it is possible that there would be bad PK interactions in some patients with particular P450 genotypes, which could derail the project.

If a single medication is efficacious against an illness then it will always be preferred to using multiple drugs in combination. Patients don't want to have to take multiple pills -- it is a source of noncompliance. Furthermore, the process of bringing medications to market requires lots of annoying steps like stability testing, figuring out how to synthesize the drugs and then generate the final dosage unit, etc; having to do that multiple times in parallel adds expense, aggravation, and increases the odds of failure.

 

[Jabberwocky]

For certain indications, drugs with a reasonable degree of selectivity are preferred. SSRIs are an example of drugs that were developed to selectively bind to one target. The problem is that it is not simple to develop drugs with selective binding profiles -- different monoamine receptors display a relatively high degree of homology.

True, even escitalopram still affects dopamine and norepinephrine re-uptake.

 

[Nagelfar]

I don't know of ANY compounds that are ONLY active at a particular subreceptor of only 1 Type, and not active anywhere else. Can you identify some?

There are a number of just D1, D2 & D3; perhaps not sub-types but *first tier* underlying types, also a few 5-HT. I'd browse through to re-identify ones I have come across in the just recent past, but I've only got a few minutes on this public computer, but clicking and reading the targets on compounds listed on WP can yield ones which I mean:

Wikipedia category: DAr agonists
Wikipedia category: DAr antagonists
Wikipedia category: 5-HTr agonists
Wikipedia category: 5-HTr antagonists
Wikipedia category: (alpha-adrenergic) α-NEr agonists
Wikipedia category: (beta-adrenergic) β-NEr agonists
Wikipedia category: (alpha-blockers) α-NEr antagonists
Wikipedia category: (beta-blockers) β-NEr antagonists

Despite the difficulties in development, the synergistic effect from doing it this way; perhaps confusing the body's tolerance system to any one of them due to the upstream and downstream cascading effect profile of them all in tandem.

I'll have more points tomorrow.

 

[serotonin2A]

I guess what I am not following is why for example you think it would be more productive to try to develop three seperate selective ligands for a combination therapy vs. developing a single molecule that hits all three sites? The former route offers many more chances to fail due to safety, PK, or efficacy issues. Having one drug with multiple targets allows you to take advantage of synergistic interactions.

 

[Limpet_Chicken]

One thing that surprises me is how much DAergic action seems to be utterly ignored when it comes to antidepressants, so much so that it almost seems as if companies might be actively rejecting compounds that are DA releaser or reuptake inhibitors
and other mechanisms of DAergic positive modulation seem ignored too (thinking things like BPAP, PEPAP, for example, that cause greater quantities of dopamine to be released per action potential-induced signalling event without either corresponding
reuptake inhibition or directly effecting monoamine release, just resulting in more neurotransmitter released when it would already be release

SSRIs strike me as really crude and dirty drugs, relying as they are thought to, on bludgeoning the 5HT1a presynaptic sites, until downregulation occurs, by the transporter blockade.

Not as rotten a concept as ECT though..damn..I can't help but feel someone, somewhere along the lines thought something like 'hey, if we kick somebody's fucking face in, they will be too busy thinking about how much that broken nose and shattered jawbone hurts to even think about their depression'

Not much better than cancer surgery using a 12-gauge. Sure, the tumor might be gone, but so is a fist-sized chunk of the patient where their liver/kidney/pancreas/lungs used to be.
Or treating E.g bone cancer by just cutting off the patients arms and or legs.

I don't remember offhand, but did josef mengele have any kids, by any chance? (non-yid-kids with their full complement of internal organs I mean)

 

[Nagelfar]

One thing that surprises me is how much DAergic action seems to be utterly ignored when it comes to antidepressants

I think abuse potential is a larger scare for the pharms considering the huge bite from the war on drugs.

Not as rotten a concept as ECT though..damn..

I've watched several very modern, up-to-date recent specials on ECT and it's actually quite a positive for neuronal growth and efficacy in the depression dept. Have you heard of rTMS or deep TMS? Instead of electricity, they use magnets to induce seizure, it's early enough that they haven't brought it up to the same efficacy as ECT, but they keep getting closer, and the side effects are much more muted if nonexistent

I guess what I am not following is why for example you think it would be more productive to try to develop three seperate selective ligands for a combination therapy vs. developing a single molecule that hits all three sites? The former route offers many more chances to fail due to safety, PK, or efficacy issues. Having one drug with multiple targets allows you to take advantage of synergistic interactions.

I just figure scientific research, esp. when it comes to biology and something as complex as the brain, should try many different things instead of settling on one way of doing something, try something a little unusual despite the apparent draw backs, 'cause you never know. It should be given one honest try in a small population; but which I mean, through study of what receptors purely garner positive effects when agonized and what ones oppose elevated mood and should be antagonist, in a very specific, piecemeal way. It seems many of the multiple target drugs have affinity or at least one site that may work to make depression worse but are overwhelmed by the higher affinity or larger amount of targets elsewhere. Making certain none of which are utilized and each receptor affinity controlled by a different rate at which it would metabolize, etc. would be a novel direction to understanding the whole issue better empirically & concretely, not just theorizing it away.

 

[Limpet_Chicken]

I've heard a lot of cases where ECT has resulted in very serious side effects, like long-term losses of memory, etc.

Doing it with TMS seems a lot like it might be a less crude alternative to ECT.

And re-abuse potential, unfortunately you may be right. But there does seem a distinct lack of SD, ND and SNDRI type medications.
And then, like I said, there are activity-enhancers like BPAP and PPAP *typo before, PEPAP* is an opioid related to pethidine, *PPAP is the catecholaminergic activity enhancer, and the compound that I wished to refer to. The two have absolutely fuck all to do with each other.

These activity-enhancer type drugs, although thus far there are not many known, don't result in the large elevations seen with drugs which either cause catecholamine efflux, or inhibit reuptake (thinking DARIs here mostly) or fuck about w/ VMATs.
So given that they only cause an increased quantity of neurotransmitter to be released with each discharge, when there is already a naturally occuring release of neurotransmitter (or of course, co-administered stimulant...christ...bet these would be abusable as hell *IF* one were to say, smoke crack, take meth along with them) but on their own I bet they don't have anything like the same amount of abuse potential as do strong DA releaser/reuptake inhibitors.

I just think that SOME dopaminergic activity, as say, a triple reuptake inhibitor, even if its a lesser component rather than the main mode of action, would probably be a lot more effective.

 

[Nagelfar]

These activity-enhancer type drugs, although thus far there are not many known, don't result in the large elevations seen with drugs which either cause catecholamine efflux, or inhibit reuptake (thinking DARIs here mostly) or fuck about w/ VMATs.
So given that they only cause an increased quantity of neurotransmitter to be released with each discharge, when there is already a naturally occuring release of neurotransmitter (or of course, co-administered stimulant...christ...bet these would be abusable as hell *IF* one were to say, smoke crack, take meth along with them) but on their own I bet they don't have anything like the same amount of abuse potential as do strong DA releaser/reuptake inhibitors.

I just think that SOME dopaminergic activity, as say, a triple reuptake inhibitor, even if its a lesser component rather than the main mode of action, would probably be a lot more effective.

I think of the DAT allosteric modulators, specifically: 3′-Oxo-8-methyl-spiro{8-azabicyclo[3.2.1]octane-3,5′-isoxazolidine} that change DAT from occluded to accepting of ligands, would be a mighty adjunct/potentiator as well.