Will we synthesise any dramatically new drugs in the future?

[heymoon999]

Of course I realise new drugs are being created all the time, but they're all similar right? Like drugs like 2cb and other RCs are pretty similar to each other and to other hallucinogens, right? I've been saving certain conventional drugs for later in life, such as dxm and dmt, bc I love the idea of a completely new drug experience that is different to other drugs. Is this wise or will there be any new drugs created that have dramatically different effects? I get the feeling we are pretty much done with all the possible ways we can mess with the mind chemically, is this right?

To what extent will drugs ever be different? Will there ever be anything new as different to the drugs around today as say, lsd is to dmt or mdma? not familiar with pharmacology at all so asking the experts.

 

[sekio]

Of course I realise new drugs are being created all the time, but they're all similar right?

it depends how you define 'similar'. there are psychoactive drugs with novel structures that come out on a semi regular basis. certainly it is easier for clandestine chemists to develop analogues of known "fun" drugs but the pharma companies do novel research that gets spun into grey market stuff (c.f. drugs like AH7921, U-47700, JWH analogs, diphenidine)

I get the feeling we are pretty much done with all the possible ways we can mess with the mind chemically, is this right?

considering the list of stuff we don't know about the brain is much longer than the list of stuff we do know... that's a rather lofty viewpoint to take.

"chemical space" (the set of all possible molecules that can be accessed by known synthetic methods) is Really Big and getting bigger every day as people discover new reactions and compounds. so it's not really possible to say "well, we've done all the chemistry there is to discover, it's a closed book". and if you haven't made "biologically useful" quantities of every possible molecule to screen as drugs, you can't say you've explored the space.

 

[Dresden]

Probably, but I'd say we've already discovered almost all if not all of the different classes of drugs. Like sekio said, organic drug chemistry and pharmacology is pretty much infinite, especially now (soon anyway), that genetically modified yeast can, using sugar and water, brew any molecule a plant can.

 

[tryp2fun]

Of course I realise new drugs are being created all the time, but they're all similar right? Like drugs like 2cb and other RCs are pretty similar to each other and to other hallucinogens, right? I've been saving certain conventional drugs for later in life, such as dxm and dmt, bc I love the idea of a completely new drug experience that is different to other drugs. Is this wise or will there be any new drugs created that have dramatically different effects? I get the feeling we are pretty much done with all the possible ways we can mess with the mind chemically, is this right?

To what extent will drugs ever be different? Will there ever be anything new as different to the drugs around today as say, lsd is to dmt or mdma? not familiar with pharmacology at all so asking the experts.

Exploring Chemical Space for Drug Discovery Using the Chemical Universe Database

Jean-Louis Reymond * and Mahendra Awale
Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, 3012 Berne, Switzerland
ACS Chem. Neurosci., 2012, 3 (9), pp 649–657
DOI: 10.1021/cn3000422
Publication Date (Web): April 25, 2012
Copyright © 2012 American Chemical Society

Herein we review our recent efforts in searching for bioactive ligands by enumeration and virtual screening of the unknown chemical space of small molecules. Enumeration from first principles shows that almost all small molecules (>99.9%) have never been synthesized and are still available to be prepared and tested. We discuss open access sources of molecules, the classification and representation of chemical space using molecular quantum numbers (MQN), its exhaustive enumeration in form of the chemical universe generated databases (GDB), and examples of using these databases for prospective drug discovery. MQN-searchable GDB, PubChem, and DrugBank are freely accessible at www.gdb.unibe.ch.

In this paper they estimate that there could be 10^60 small molecules that have drug-like properties. There are now only ~10^7 known chemical compounds. Think there's anything to be discovered?

 

[nAON]

Probably, but I'd say we've already discovered almost all if not all of the different classes of drugs. Like sekio said, organic drug chemistry and pharmacology is pretty much infinite, especially now (soon anyway), that genetically modified yeast can, using sugar and water, brew any molecule a plant can.

That's a logical fallacy. There are uncountable numbers of potential chemicals that have never been synthesized, and thus have unknown biological properties, and thus have not been assigned a 'drug class' yet. Having the technical capability to synth anything is not the same as knowing wtf exactly it is you want to make.

 

[Black]

there are probably a few new classes to be explored, but finding out that something's a drug is harder than before. most compounds just run through a specific assay (to quantify its action on a known target) and tasting (or testing it on your self like hofmann did) your newly made compound isn't really acceptable anymore.

 

[PsychedelicWizard]

http://en.wikipedia.org/wiki/Nanotechnology

Forget consuming drugs like we do now, just have tiny robots directly cause the effects you want, without side effects.

 

[nAON]

http://en.wikipedia.org/wiki/Nanotechnology

Forget consuming drugs like we do now, just have tiny robots directly cause the effects you want, without side effects.

Could you elaborate on the mechanism for this?

 

[Dresden]

Idk but by applying a certain amount of electric current as with an implantable "pacemaker" for your head, for example, to a particular area of the brain is just as reinforcing as doing addictive drugs. Vibrational and light frequencies may also one day be used to control mood or even combat diseases such as cancer or radiation sickness, which let's face it, the people on our planet will likely be exposed to much higher levels of radioactivity than we are today (with nuclear bombs and melted down nuclear power plants and whatnot).

 

[endotropic]

If you consider DMT substantially different from 2-CB and other RC serotonergic psychedelics (based on what? duration of action? lack of oral bioavailability?) then yes, we will undoubtedly find dramatically new drugs in the future.

We will also find new drugs in the currently known pharmacological classes but with off target action that leads to a different subjective experience compared to anything we have now. This already happens all the time. I would consider MDMA dramatically different from methamphetamine for example, but pharmacologically they only differ in the balance of monoamine release and the addition of 5-HT2A agonism with MDMA.

The really interesting question to me is whether we'll find a completely novel mechanism that can produce recreational effects on its own. Personally I think there's a good chance that it will happen, and I would put my money on something targeting intracellular processes. On the other hand it's been a damn long time since a recreational drug with a truly novel mechanism was discovered. NMDA antagonists might be the most recent class, and those were discovered in the 60's.

 

[PsychedelicWizard]

Could you elaborate on the mechanism for this?

Let us compare it to for example amphetamine.

Instead of eating a pill containing amphetamine salts, you'd instead eat a pill containing billions of microscopic robots that would do the same thing to the brain, although without side effects, as well as lasting as long as you desired.

 

[Yeetbeat]

Let us compare it to for example amphetamine.

Instead of eating a pill containing amphetamine salts, you'd instead eat a pill containing billions of microscopic robots that would do the same thing to the brain, although without side effects, as well as lasting as long as you desired.

I understand what you're saying, though (in my limited understanding) you hit a brick wall when you consider that the desired effects rely on receptor agonism/antagonism caused by particular molecules. Then consider the size of the robots required to perform the same action as an LSD molecule, which is only a number of atoms as it is.

Just my thoughts.

 

[nAON]

Let us compare it to for example amphetamine.

Instead of eating a pill containing amphetamine salts, you'd instead eat a pill containing billions of microscopic robots that would do the same thing to the brain, although without side effects, as well as lasting as long as you desired.

How exactly would those robots do the same thing to the brain without the side effects? Through what mechanism would they interact with receptors/neurotransmitter stores/neurones? How would they get into, and transport themselves around the brain in the first place?

 

[AyahuascaForLunch]

The really interesting question to me is whether we'll find a completely novel mechanism that can produce recreational effects on its own. Personally I think there's a good chance that it will happen, and I would put my money on something targeting intracellular processes. On the other hand it's been a damn long time since a recreational drug with a truly novel mechanism was discovered. NMDA antagonists might be the most recent class, and those were discovered in the 60's.

When were kappa-opioid agonists discovered? It certainly took a while before Salvia's pharmacology was eventually figured out in the 90s.

Either way, I'm fairly confident we have a lot of mixed-MOA drugs left to discover - look at Ibogaine's promiscuous pharmacology for example, and synthetic ibogoids are only one of many potential starting points to explore.

Personally I'd like a chemical that acts as both a 5ht2a agonist and NMDA antagonist 'only', ie. without the full plethora of receptors Ibogaine hits. Or perhaps a GABA agonist and k-opioid agonist rolled into one, something similar to a Salvia experience but without the fear it often brings. And this is before I start imagining the possibilities of drugs with both an appealing recreational profile and a beneficial nootropic action.

 

[knockout_mice]

Possibly better versions of current drugs:

5-HT2A positive allosteric modulators
Nicotine alpha7 positive allosteric modulators
Selective dopamine agonists (e.g. D4)
Selective delta opioid agonists and kappa antagonists
Selective GABA PAMs (mimicking the effects of ethanol without sleepiness / oxidative stress)
Selective adenosine A2A antagonists
Sigma ligands
Better ampakines
Melatonin antagonists / Orexin agonists

 

[Nagelfar]

I'm hoping science discovers more 'orphan' receptors (like the PCP ligand site for NMDAR antagonism). Because the ligands won't light up, there may be a plethora of them lying dormant and undiscovered. Dissociative Anaesthesia is one of the strangest, and colloquially potentially most spiritual, of the altered states, and there is no known naturally occurring endogenous molecular ligand for it. There may be one, but it's undiscovered. My personal belief is, there is probably one for it, but because of the different ways that the voltage channels can be bridged and gated, that there are extremely obscure ones that indeed are genuinely "orphan" (have no naturally evolved/intended purpose) without any endogenous agonist, discovered or not. These are the ones that would pique my interest most.

Just how pervasive the glutamate system is, and how closely the DXM type molecules are to the natural morphinan opioids, make me believe that the PCP site isn't "authentically" orphan, just that the particular strain of 'paternity' from said endogenous chemicals is currently unknown.

 

[blazR]

Melatonin antagonists / Orexin agonists

I get the rest of your suggestions, I think.. But why would anyone want to antagonize Melatonin receptors?

 

[nAON]

I'm hoping science discovers more 'orphan' receptors (like the PCP ligand site for NMDAR antagonism). Because the ligands won't light up, there may be a plethora of them lying dormant and undiscovered. Dissociative Anaesthesia is one of the strangest, and colloquially potentially most spiritual, of the altered states, and there is no known naturally occurring endogenous molecular ligand for it. There may be one, but it's undiscovered. My personal belief is, there is probably one for it, but because of the different ways that the voltage channels can be bridged and gated, that there are extremely obscure ones that indeed are genuinely "orphan" (have no naturally evolved/intended purpose) without any endogenous agonist, discovered or not. These are the ones that would pique my interest most.

Just how pervasive the glutamate system is, and how closely the DXM type molecules are to the natural morphinan opioids, make me believe that the PCP site isn't "authentically" orphan, just that the particular strain of 'paternity' from said endogenous chemicals is currently unknown.

There are loads of complex transporters at work that help regulate NMDA-R which haven't been targetted much. For example ASC-1 which moves the coagonists DSerine and Glycine is being worked on by various pharma companies for schizophrenia currently, and the co-agonist sites directly may have interesting effects if blocked.

 

[Bomb319]

Common sense tells me that we can only produce drugs that are already analogous to chemicals used by the brain. It's not possible to create a chemical to have specifically tailored effects on the brain if the brain doesn't already use a similar pathway. The brain wouldn't have any mechanism for binding/receiving it. However, it should absolutely be possible with more specific and detailed knowledge of drug/receptor pharmacology to be able to create an analogue drug with very specific actions - possible entirely eliminating undesired effects while maximising therapeutic ones.

We have already done this to some extent. There is an opiate whose name currently eludes me, that was designed to express ALL major molecular factors that determine how strong an opiate will be. This drug was quite quickly banned, and is not discussed much at all - even among researchers. Why? It can simply be swallowed, yet produce a way more intense and long-lasting rush than heroin. It's so addictive that it couldn't be used even as medicine. This is completely different from simply using very potent opioids like fentanyl derivatives. Those allow you to use much less of the drug and may bind tightly, but still produce a ceiling effect when it comes to subjective euphoria. This drug apparently is not like that, and directly activates the brain's pleasure centers extremely powerfully and persistently. It would completely and disastrously hook anyone who took it, no matter what the purpose. Of course knowing this, I obviously want to try it even though I should know better; nothing good could possibly come of it.

 

[sekio]

Was it an opioid, or was it one of the dopamine D1-selective agonists you're thinking of?

The only reason I ask is because, as far as I know, chemists know how to make strong opioids, but what makes them euphoric is still up for debate. (Well, aside from stuff like speed of administration to the blood, etc).

Maybe it was ketobemidone (a suped up version of pethidine), or etonitazine, or one of the Bentley compounds (etorphine?)

I know there's permanently-binding opioid agonists, too, but those actually develop tolerance even faster than "normal" opioids.

(If it's a schedule I drug you're thinking of, look through the Controlled Drugs and Substances Act?)