Fertile
Bluelighter
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'A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude)'
Molecular Pharmacology
2015 Aug;88(2):401-20.
doi: 10.1124/mol.115.099291.
Found that not only does methaqualone bind to α1,2,3,5β2,3γ2S as a positive allosteric modulator (like benzodiazepines) but also that it binds to α4,6β1,2,3δ being a negative allosteric modulator at α6β1δ (which will produce actuall;y cause stimulation BUT it's a SUPERagonist at the α4β3δ juncture.
OK so kind of interesting, but what's the practical use?
We it turns out that it's possible to design benzodiazepines that can be selective to the α1,α2,3 and/or α5 that are are also superagonists.
The key problem when trying to emulate the effects of alcohol is that the positive effects of alcohol are shown to be α5 mediated. But not just α5β1 - so you need a ligand that is a PAM at the α5β1, α5β2 & α5β3 and a 1,5-benzodiazepine won't do that. That is why pyrazolam had an unusual (and problematic) dose-response curve i.e. it does nothing until you reach about 0.3mg/kg but then 0.6mg/kg feels as euphoric (if that the right word) as having drunk an entire bottle of vodka.
I hasten to add that we were able to find that alcohol also binds to the α1β1, α1β2 & α1β3 and all of the negative effects of alcohol (mood lability, ataxia, retrograde amnesia, anterograde amnesia, aggression, syncope, pronounced hypnotic symptoms and increased appetite).
I don't know if methaqualone caused any or all of the above negative effects I mention but I'm pretty sure that it's the superagonism that resulted in the terrific euphoria and feelings of wellbeing users reported. I'm also wondering if the euphoria is also mediated by the ability of methaqualone to increase serotonin levels (and I also think that said increase played a significant role in it's use as a hypnotic) because it certainly did act in concert with serotonin to mediate many of it's effects.
'Serotonin as a facilitatory neurotransmitter in the anticonvulsant activity of methaqualone'
Physiolgical Behavior.
1989 Jul;46(1):105-6.
doi: 10.1016/0031-9384(89)90331-4.
'DARK Classics in Chemical Neuroscience: Methaqualone'
ACS Chemical Neuroscience 2023, 14, 3, 340–350
Publication Date:January 18, 2023
doi.org/10.1021/acschemneuro.2c00697
Molecular Pharmacology
2015 Aug;88(2):401-20.
doi: 10.1124/mol.115.099291.
Found that not only does methaqualone bind to α1,2,3,5β2,3γ2S as a positive allosteric modulator (like benzodiazepines) but also that it binds to α4,6β1,2,3δ being a negative allosteric modulator at α6β1δ (which will produce actuall;y cause stimulation BUT it's a SUPERagonist at the α4β3δ juncture.
OK so kind of interesting, but what's the practical use?
We it turns out that it's possible to design benzodiazepines that can be selective to the α1,α2,3 and/or α5 that are are also superagonists.
The key problem when trying to emulate the effects of alcohol is that the positive effects of alcohol are shown to be α5 mediated. But not just α5β1 - so you need a ligand that is a PAM at the α5β1, α5β2 & α5β3 and a 1,5-benzodiazepine won't do that. That is why pyrazolam had an unusual (and problematic) dose-response curve i.e. it does nothing until you reach about 0.3mg/kg but then 0.6mg/kg feels as euphoric (if that the right word) as having drunk an entire bottle of vodka.
I hasten to add that we were able to find that alcohol also binds to the α1β1, α1β2 & α1β3 and all of the negative effects of alcohol (mood lability, ataxia, retrograde amnesia, anterograde amnesia, aggression, syncope, pronounced hypnotic symptoms and increased appetite).
I don't know if methaqualone caused any or all of the above negative effects I mention but I'm pretty sure that it's the superagonism that resulted in the terrific euphoria and feelings of wellbeing users reported. I'm also wondering if the euphoria is also mediated by the ability of methaqualone to increase serotonin levels (and I also think that said increase played a significant role in it's use as a hypnotic) because it certainly did act in concert with serotonin to mediate many of it's effects.
'Serotonin as a facilitatory neurotransmitter in the anticonvulsant activity of methaqualone'
Physiolgical Behavior.
1989 Jul;46(1):105-6.
doi: 10.1016/0031-9384(89)90331-4.
'DARK Classics in Chemical Neuroscience: Methaqualone'
ACS Chemical Neuroscience 2023, 14, 3, 340–350
Publication Date:January 18, 2023
doi.org/10.1021/acschemneuro.2c00697