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N&PD Moderators: Skorpio | thegreenhand
Are there new categories of drugs waiting to be discovered?
- Thread starter DroneLore
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Solipsis
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IMO yes definitely.
Relatively speaking it is very efficient to go with nature's / evolution's products and modify them and run with that. For some more unrelated compounds like diphenidines the design follows such a clear rationale that discovering pharmacological activity is really not an accidental discovery at all...
How drug companies actually design drugs, like say DXM baffles me and I'd love for an NSPer to try and explain that basically, like using some examples of tricks used - do they just theorize a pharmacophore and comply with that especially at critical points? Or was that just from having stumbled the opioid levo isomer, already checking out morphinans? I mean: some pharmaceuticals just look pretty novel in their structure and I don't know if that is just because I don't know the compounds they are derived from or what tricks are used in drug design to successfully guess some of the more imaginative ones.
But it's relatively also so recent a development to use computational models (and also x-ray crystallography of complex receptor structures) to help us figure out binding of drugs to those receptors that for a long time I think it just has been extremely difficult or pretty much impossible to come up with totally new classes without using the sort of predictions from known compounds.
What evolution produced is apparently in some ways an optimalization process even though it goes by increments of accidental mutations etc... so that should explain why nature came up with lysergic compounds for example... but considering the various ways psychedelics can bind to the 5-HT2A receptor, and the relatively few natural psychedelic families that we know of (psy tryptamines of course look a LOT like serotonin itself but this does not necessarily have to be so: phenethylamines are already different and surprisingly the way they may bind really often does not overlap with how you might see similarities between these molecules and would suggest a pharmacophore...
So I think while there are limits imposed by what the receptor and it's amino acid residues tolerate and 'select', the list should be by no means exhausted. I personally hope that they can hook up computational software loaded with e.g. the 5-HT2A receptor's structure to LSTM networks (artificial intelligence sort of) and have it come up with ligands and optimalize the computated binding and then screen the absolute winners for looking interesting and particularly easy to synth...
I haven't heard that suggestion before but it seems a logical next step considering state of the art developments in other fields. I'd like to ask Nichols about this, seems like an interesting question considering the - sorry for saying so - pedestrian or even unscientific questions he even seems to answer.
EDIT:
Oh never mind, they are already trying this - even on 5-HT2A: https://arxiv.org/pdf/1701.01329.pdf page 16 and it works - however this was still done by applying the LSTM to basically the sort of logic that they used to come up with diphenidines IMO - what I would like to see is not just LSTM applied to a large pre-existing dataset but I guess something more like an aversary network, where one part generates ligands as a live dataset but another part of the network actually checks it using 3D computations of 5-HT2A which I don't think is used here, then feeds back information to optimalize the process... to actually evolve to coming up with new 'good ideas' based on what makes the idea good and going beyond inferring it from other good ideas. It's a major difference, for example when they would discover a yet unknown receptor and somehow also discover that it is potentially a revolutionary drug target, then it would be sweet if you had to elucidate it's structure but not even any endogenous ligands to come up with drugs.
A caveat though is that you would have no idea about function or what is the active site(s) of the receptor, that would still have to be screened and found out differently. Though if the activated states and inactive state would be known the next step might be to computate something that can achieve this change in state.
Relatively speaking it is very efficient to go with nature's / evolution's products and modify them and run with that. For some more unrelated compounds like diphenidines the design follows such a clear rationale that discovering pharmacological activity is really not an accidental discovery at all...
How drug companies actually design drugs, like say DXM baffles me and I'd love for an NSPer to try and explain that basically, like using some examples of tricks used - do they just theorize a pharmacophore and comply with that especially at critical points? Or was that just from having stumbled the opioid levo isomer, already checking out morphinans? I mean: some pharmaceuticals just look pretty novel in their structure and I don't know if that is just because I don't know the compounds they are derived from or what tricks are used in drug design to successfully guess some of the more imaginative ones.
But it's relatively also so recent a development to use computational models (and also x-ray crystallography of complex receptor structures) to help us figure out binding of drugs to those receptors that for a long time I think it just has been extremely difficult or pretty much impossible to come up with totally new classes without using the sort of predictions from known compounds.
What evolution produced is apparently in some ways an optimalization process even though it goes by increments of accidental mutations etc... so that should explain why nature came up with lysergic compounds for example... but considering the various ways psychedelics can bind to the 5-HT2A receptor, and the relatively few natural psychedelic families that we know of (psy tryptamines of course look a LOT like serotonin itself but this does not necessarily have to be so: phenethylamines are already different and surprisingly the way they may bind really often does not overlap with how you might see similarities between these molecules and would suggest a pharmacophore...
So I think while there are limits imposed by what the receptor and it's amino acid residues tolerate and 'select', the list should be by no means exhausted. I personally hope that they can hook up computational software loaded with e.g. the 5-HT2A receptor's structure to LSTM networks (artificial intelligence sort of) and have it come up with ligands and optimalize the computated binding and then screen the absolute winners for looking interesting and particularly easy to synth...
I haven't heard that suggestion before but it seems a logical next step considering state of the art developments in other fields. I'd like to ask Nichols about this, seems like an interesting question considering the - sorry for saying so - pedestrian or even unscientific questions he even seems to answer.
EDIT:
Oh never mind, they are already trying this - even on 5-HT2A: https://arxiv.org/pdf/1701.01329.pdf page 16 and it works - however this was still done by applying the LSTM to basically the sort of logic that they used to come up with diphenidines IMO - what I would like to see is not just LSTM applied to a large pre-existing dataset but I guess something more like an aversary network, where one part generates ligands as a live dataset but another part of the network actually checks it using 3D computations of 5-HT2A which I don't think is used here, then feeds back information to optimalize the process... to actually evolve to coming up with new 'good ideas' based on what makes the idea good and going beyond inferring it from other good ideas. It's a major difference, for example when they would discover a yet unknown receptor and somehow also discover that it is potentially a revolutionary drug target, then it would be sweet if you had to elucidate it's structure but not even any endogenous ligands to come up with drugs.
A caveat though is that you would have no idea about function or what is the active site(s) of the receptor, that would still have to be screened and found out differently. Though if the activated states and inactive state would be known the next step might be to computate something that can achieve this change in state.
Last edited:
Holy shit!! Thank you for such a thought out answer. That is a lot of logic to work through, a lot of jargon to sort out, and a decent motivation to stay sober for at least a little while
tantric
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read about Bremelanotide, agonist of the melanocortin 3 receptor and the melanocortin 4 receptor.
but unlike other prosex drugs, it works just as well for women.
L-368,899 is a drug used in scientific research which acts as a selective antagonist of the oxytocin receptor, with good selectivity over the related vasopressin receptors.[1] Unlike related drugs such as the peripherally selective L-371,257, the oral bioavailabity is high and the brain penetration of L-368,899 is rapid, with selective accumulation in areas of the limbic system. This makes it a useful tool for investigating the centrally mediated roles of oxytocin, such as in social behaviour and pair bonding, and studies in primates have shown L-368,899 to reduce a number of behaviours such as food sharing, sexual activity and caring for infants, demonstrating the importance of oxytocinergic signalling in mediating these important social behaviours
The past eight years of research has demonstrated that oxytocin nasal spray has a significant impact on human social cognition. The aim of this review is to provide critical comment on the literature using an information-processing framework. We provide a summary of fundamental assumptions of information-processing models and highlight an impressive range of consistent findings that demonstrate the impact of oxytocin nasal spray on social information processing. These findings include that oxytocin nasal spray improves the early conceptual detection of affect from social cues and improves the accurate appraisal of affect from social cues at elaborate and strategic levels of processing. There is some evidence that these effects may be particularly powerful for positive social cues. This review comments on inconsistent results that have been reported. We argue that such inconsistencies can, in part, be explained by variability across experiments in the degree to which potential extraneous confounds have been controlled, the different methods upon which studies assessed cognition, and the extent to which the focus of investigation has been on group-based outcomes. Finally, we argue that sound cognitive experimental methods can provide powerful tools to identify markers of response to oxytocin nasal spray that can be integrated into more complex circuitry models. The identification of robust markers has particular value in predicting behavioral and therapeutic response to intervention. This should now be a major focus for future research. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
but unlike other prosex drugs, it works just as well for women.
L-368,899 is a drug used in scientific research which acts as a selective antagonist of the oxytocin receptor, with good selectivity over the related vasopressin receptors.[1] Unlike related drugs such as the peripherally selective L-371,257, the oral bioavailabity is high and the brain penetration of L-368,899 is rapid, with selective accumulation in areas of the limbic system. This makes it a useful tool for investigating the centrally mediated roles of oxytocin, such as in social behaviour and pair bonding, and studies in primates have shown L-368,899 to reduce a number of behaviours such as food sharing, sexual activity and caring for infants, demonstrating the importance of oxytocinergic signalling in mediating these important social behaviours
The past eight years of research has demonstrated that oxytocin nasal spray has a significant impact on human social cognition. The aim of this review is to provide critical comment on the literature using an information-processing framework. We provide a summary of fundamental assumptions of information-processing models and highlight an impressive range of consistent findings that demonstrate the impact of oxytocin nasal spray on social information processing. These findings include that oxytocin nasal spray improves the early conceptual detection of affect from social cues and improves the accurate appraisal of affect from social cues at elaborate and strategic levels of processing. There is some evidence that these effects may be particularly powerful for positive social cues. This review comments on inconsistent results that have been reported. We argue that such inconsistencies can, in part, be explained by variability across experiments in the degree to which potential extraneous confounds have been controlled, the different methods upon which studies assessed cognition, and the extent to which the focus of investigation has been on group-based outcomes. Finally, we argue that sound cognitive experimental methods can provide powerful tools to identify markers of response to oxytocin nasal spray that can be integrated into more complex circuitry models. The identification of robust markers has particular value in predicting behavioral and therapeutic response to intervention. This should now be a major focus for future research. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.
Solipsis
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You should edit out those vendor names..
Yeah melanotan 2 sounded interesting to me for the tan but i felt really decadent for considering it hehe.
Not sure but I think recreational / psychedelic drugs were meant in the OP? Surely novel medicinal drugs are being developed..
The oxytocin thing is interesting though and I always thought it was. Is that relatively safe like boosting melatonin levels by supplementing melatonin or more iffy like messing up your hormones with steroids?
They should go for an agonist. The positively influence on processing of social cues could perhaps help people with autism or agoraphobia / social anxiety etc..
Yeah melanotan 2 sounded interesting to me for the tan but i felt really decadent for considering it hehe.
Not sure but I think recreational / psychedelic drugs were meant in the OP? Surely novel medicinal drugs are being developed..
The oxytocin thing is interesting though and I always thought it was. Is that relatively safe like boosting melatonin levels by supplementing melatonin or more iffy like messing up your hormones with steroids?
They should go for an agonist. The positively influence on processing of social cues could perhaps help people with autism or agoraphobia / social anxiety etc..
JK25
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There are 118 elements on the periodic table as of 2016. With those you can make combinations of elements to form combinations of molecules to a number we cannot even fathom. With only 118 elements you can stack them together in more than 10,000,000,000,000,000,000,000,000,000,00 (72 more zeros are needed) combinations.
So YES, there is a fuckload of chemicals still to be discovered and created.