🎄 Not the most cheerful topic, but as we see there is some connection to Christmas here. Wishing you all a great wrap-up to 2023 and a restful holiday period. Thanks again to all channel supporters and followers! Let me know any thoughts as always. www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
Thanks for the info. As a pharmacist, this information is crucial for understanding how important drug safety is, independently the of step in which we are working.
Thanks mate. Yeah the chemistry was pretty modest on this one. I'm gonna mix some easier but visual chemistry, as well as advanced organic synthesis in upcoming vids. Maybe another psychedelic (e.g. salvinorin A) as well in future. I basically have an infinite list of topis I'd like to cover, the question is time to make videos :)
@@totalsynthesis It would be great to see what's the base mechanism of action which was the reason why this drug was prescribed in first place, and made it so infamous.
@@szalonydoktor I don't think it's really. See here: www.ncbi.nlm.nih.gov/pmc/articles/PMC9780081/ "Sedation is a consistently reported effect in clinical studies of THD (see Millrine and Kishimoto, 2017), including when evaluated for efficacy against CINV (Zhang et al., 2017). It may be speculated that a general reduction in arousal level may reduce perception of nausea (involving thalamo-cortical arousal) but it is less likely to affect vomiting as this can be evoked even under general anaesthesia (Andrews et al., 1990). However, other drugs with sedative/hypnotic activity such as propofol, midazolam and olanzepine also have ‘anti-emetic’ activity in humans (Borgeat et al., 1992; Tarhan et al., 2007; Davis and Sanger, 2020) so could this be the case for THD? Propofol acts on multiple ligand-gated ion channels, including the GABAA, glycine, nicotinic and weakly, 5-HT3 receptors (Trapani et al., 2000). Positive modulation of the inhibitory function of GABAA receptors by propofol (Barann et al., 2000; Trapani et al., 2000) has been demonstrated in the NTS (McDougall et al., 2008) and the AP (Cechetto et al., 2001) and could contribute to a direct anti-emetic effect in post-operative nausea and vomiting and CINV even when propofol is administered at sub-hypnotic doses (e.g., Ewalenko et al., 1996; Gan et al., 1997; Kim et al., 2000). The sedating benzodiazepine medazoline may also be efficacious against post-operative nausea and vomiting (PONV) at sub-hypnotic doses, and like propofol modulates neuronal activity by binding to the GABAA-benzodiazepine receptor complex (Tarhan et al., 2007). Finally, the antipsychotic drug olanzapine, which also causes sedation can inhibit vomiting (Davis and Sanger, 2020 for review). This drug also antagonises activity at multiple receptors (D1, D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, α1 adrenergic, H1 and m1, m2, m3, m4 receptors) many of which may be involved in the mechanisms of vomiting although antagonism of the H1 receptor is most likely responsible for the sedative actions of olanzapine within the cerebral cortex (Davis and Sanger, 2020). With regards to THD, binding studies (see below) at a range of different receptor and enzyme targets do not suggest an ability to interact with any of the anti-emetic mechanisms suggested for propofol, medazoline or olanzapine (Kanbayashi et al., 1996). Interestingly, in silico studies suggest that THD can dock with the benzodiazepine pocket of the GABAA receptor (Asadollahi et al., 2019). These findings contrast with an inability of THD to bind to this area (Kanbayashi et al., 1996; see below) but do indicate that further studies are needed to look for an ability of THD to modulate GABAA function (see also 6.2, iii). Neurophysiological and molecular studies of the sedative/hypnotic actions of THD show that it does not appear to involve the cereblon-mediated ubiquitin/proteasome pathway (Hirose et al., 2020). However, a THD-induced depression of cortical excitatory transmission, partially mediated pre-synaptically, was observed in the absence of an effect on inhibitory transmission (ibid). Earlier animal studies differentiated THD from pentobarbital in several ways: i) THD increased slow wave sleep and rapid eye movement sleep at doses which did not induce ataxia; ii) THD did not reduce pre-optic area activity; iii) THD enhanced the sleep-inducing effect of basal forebrain stimulation (Frederickson et al., 1977; Kaitin, 1985). THD has an acute, rapid onset sedative/hypnotic effect with a different profile from barbiturates. The sedative/hypnotic effects in both human and animal studies suggest a central action involving suppression of excitatory neurotransmission which if it occurred in critical parts of pathways receiving stimuli inducing nausea or vomiting (e.g., NTS, AP) could also directly affect induction of nausea and/or vomiting (rather than indirectly through reduced arousal)."
@@totalsynthesis Thank you for your effort. So the answer is "we don't know" 😁. Thought mechanism will be known at this point. I was reading about speculation on THD as H1 antagonist and GABAa agonist many years ago
Great work ! To be fair the side effect is very specific, especialy compared to what thoes nazi must have had already tested so it looked safe for them lol
🎄 Not the most cheerful topic, but as we see there is some connection to Christmas here. Wishing you all a great wrap-up to 2023 and a restful holiday period.
Thanks again to all channel supporters and followers! Let me know any thoughts as always.
www.patreon.com/totalsynthesis; instagram.com/totalsynthesis_official/
Thanks for the info. As a pharmacist, this information is crucial for understanding how important drug safety is, independently the of step in which we are working.
Thanks for watching!
This is my absolutely favourite type of content on yt. Please never stop making these. The more you go into the MOA, the better
Thank you! This video wasnt shown to many viewers for some reason but comments like yours are very encouraging, I will definitely make more in future
More drug scandle videos please! Really enjoyed this one
Awesome, thanks. There is some other big and small stuff, I will put on my list for 2024 :)
The fact that the _shape_ of a molecule can be understood and then tailored to suit is very nearly miraculous.
Super cool
Thank you so much for the video, i especially love the part explaining in deep details the biochemical mechanism
Thanks for your comment! Glad you enjoyed this
new total synthesis video
💕💕💕
This IS a miracle drug, but they did not practice safety at all! It was only dangerous during a few weeks of pregnacy.
Exactly, although use later in pregnancy did not lead to those obvious malformations but some other detrimental effects as well
Thalidomide is a very good drug for sleep, rivals the barbs, anyone who has tried them will agree
I like your videos
Thanks mate!
Thank you for the excellent video!
Thanks for making it clear out of the gate that there is no way for pregnant people to ingest this safely!
*Pregnant Women
Love your channel🙏🙏
Thank you 🥰
Very interesting background information, though the chemistry was pretty simple due to a non-complex target molecule. What do you have planned next?
Thanks mate. Yeah the chemistry was pretty modest on this one. I'm gonna mix some easier but visual chemistry, as well as advanced organic synthesis in upcoming vids. Maybe another psychedelic (e.g. salvinorin A) as well in future. I basically have an infinite list of topis I'd like to cover, the question is time to make videos :)
The literature is about to learn how to make these compounds like crazy, trust me...
didnt walter white teach this to his students
I'm curious about mechanism of action as sedative. There's little info on how it works on CNS. It would be a good idea to explain this mechanism
Yeah I do agree I actually didnt find much info on this one when researching, I'll check
@@totalsynthesis It would be great to see what's the base mechanism of action which was the reason why this drug was prescribed in first place, and made it so infamous.
@@szalonydoktor I don't think it's really. See here: www.ncbi.nlm.nih.gov/pmc/articles/PMC9780081/
"Sedation is a consistently reported effect in clinical studies of THD (see Millrine and Kishimoto, 2017), including when evaluated for efficacy against CINV (Zhang et al., 2017). It may be speculated that a general reduction in arousal level may reduce perception of nausea (involving thalamo-cortical arousal) but it is less likely to affect vomiting as this can be evoked even under general anaesthesia (Andrews et al., 1990). However, other drugs with sedative/hypnotic activity such as propofol, midazolam and olanzepine also have ‘anti-emetic’ activity in humans (Borgeat et al., 1992; Tarhan et al., 2007; Davis and Sanger, 2020) so could this be the case for THD? Propofol acts on multiple ligand-gated ion channels, including the GABAA, glycine, nicotinic and weakly, 5-HT3 receptors (Trapani et al., 2000). Positive modulation of the inhibitory function of GABAA receptors by propofol (Barann et al., 2000; Trapani et al., 2000) has been demonstrated in the NTS (McDougall et al., 2008) and the AP (Cechetto et al., 2001) and could contribute to a direct anti-emetic effect in post-operative nausea and vomiting and CINV even when propofol is administered at sub-hypnotic doses (e.g., Ewalenko et al., 1996; Gan et al., 1997; Kim et al., 2000). The sedating benzodiazepine medazoline may also be efficacious against post-operative nausea and vomiting (PONV) at sub-hypnotic doses, and like propofol modulates neuronal activity by binding to the GABAA-benzodiazepine receptor complex (Tarhan et al., 2007). Finally, the antipsychotic drug olanzapine, which also causes sedation can inhibit vomiting (Davis and Sanger, 2020 for review). This drug also antagonises activity at multiple receptors (D1, D2, D3, D4, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, α1 adrenergic, H1 and m1, m2, m3, m4 receptors) many of which may be involved in the mechanisms of vomiting although antagonism of the H1 receptor is most likely responsible for the sedative actions of olanzapine within the cerebral cortex (Davis and Sanger, 2020).
With regards to THD, binding studies (see below) at a range of different receptor and enzyme targets do not suggest an ability to interact with any of the anti-emetic mechanisms suggested for propofol, medazoline or olanzapine (Kanbayashi et al., 1996). Interestingly, in silico studies suggest that THD can dock with the benzodiazepine pocket of the GABAA receptor (Asadollahi et al., 2019). These findings contrast with an inability of THD to bind to this area (Kanbayashi et al., 1996; see below) but do indicate that further studies are needed to look for an ability of THD to modulate GABAA function (see also 6.2, iii).
Neurophysiological and molecular studies of the sedative/hypnotic actions of THD show that it does not appear to involve the cereblon-mediated ubiquitin/proteasome pathway (Hirose et al., 2020). However, a THD-induced depression of cortical excitatory transmission, partially mediated pre-synaptically, was observed in the absence of an effect on inhibitory transmission (ibid). Earlier animal studies differentiated THD from pentobarbital in several ways: i) THD increased slow wave sleep and rapid eye movement sleep at doses which did not induce ataxia; ii) THD did not reduce pre-optic area activity; iii) THD enhanced the sleep-inducing effect of basal forebrain stimulation (Frederickson et al., 1977; Kaitin, 1985). THD has an acute, rapid onset sedative/hypnotic effect with a different profile from barbiturates. The sedative/hypnotic effects in both human and animal studies suggest a central action involving suppression of excitatory neurotransmission which if it occurred in critical parts of pathways receiving stimuli inducing nausea or vomiting (e.g., NTS, AP) could also directly affect induction of nausea and/or vomiting (rather than indirectly through reduced arousal)."
@@totalsynthesis Thank you for your effort. So the answer is "we don't know" 😁. Thought mechanism will be known at this point. I was reading about speculation on THD as H1 antagonist and GABAa agonist many years ago
fascinating stuff
7:50
Great work ! To be fair the side effect is very specific, especialy compared to what thoes nazi must have had already tested so it looked safe for them lol
Yep that's absolutely right
This was the first thing that came to mind 😂
Im so annoyed that the only way i noticed this video is your community post.
Man I dont know why but the algo hasnt been liking my past videos, it's not recommending to my subs very much 😂
But thats good feedback for me to continue doing some video-related community posts once in a while
@@totalsynthesis I even have notifications turned on... But keep putting out the amazing content!
thank you!! @@abs0lute-zer061
Teratogenic drug