CrazyEngineer
Bluelighter
- Joined
- May 23, 2015
- Messages
- 57
Does anyone have experience with α5IA (or other selective GABA-A-a5 antagonists)?
So, I was doing Internet research on GABA-A receptors in the process of trying to explain the respective tolerance and OD risk profiles of zolpidem compared to benzos to somebody, and I stumbled on this gem. It's apparently a powerful inverse agonist of GABA-A subtype a5, while having weak partial agonist or inverse agonist activities at a1, a2, and a3-subtype receptors. Doing some more research, it appears that the a1 subtype mostly modulates sedation, a2 and a3 modulate anxiety, and that a5 affects memory and cognition. Benzodiazepines apparently activate all four receptors, causing sedation, anxiolysis, and also some degree of acute and cumulative impairment of memory and cognition. Zolpidem is reasonably selective for a1, so it knocks you out without really relieving anxiety or messing with your brain. By contrast, α5IA is an inverse agonist at a5 and a very weak partial agonist at a2; it would thus appear that α5IA would have a very weak anxiolytic effect while boosting memory and cognition.
I did some more research and found a few mouse and human studies of the stuff. They tested it in mice with Down's syndrome, and found that daily 5mg/kg injections of α5IA for two weeks repaired basically all of the deficits in several immediate early genes associated with memorization (and thus helped the mice achieve much faster times through a standard water maze). Some basic human trials have been done for safety and nootropic efficacy, and the results were interesting. Apparently α5IA did nothing or worse for elderly people (tests showed that a 4mg dose actually worsened performance on a paired-associate learning task for elderly patients), but it basically undid cognitive impairment due to drunkenness in young, healthy volunteers. As far as I can tell, the big risk is that one of its metabolites has a solubility in water of around 600 ng/mL, which is high enough that dramatically increased doses of α5IA caused some degree of kidney damage which precluded long-term dosing regimes in subjects. It's also apparently well-tolerated in people up to at least 6mg in the short term, and it might turn out to be a really useful drug.
I was wondering if anyone on here either has personal experience with the stuff, or has better medical knowledge of what happens when you shut down GABA-A-a5. It's currently only available for $28 per milligram, but I poked a friend of a friend who's going to grad school for chemistry about the feasibility of a synthesis for it and would like opinions on whether it's worth the trouble
So, I was doing Internet research on GABA-A receptors in the process of trying to explain the respective tolerance and OD risk profiles of zolpidem compared to benzos to somebody, and I stumbled on this gem. It's apparently a powerful inverse agonist of GABA-A subtype a5, while having weak partial agonist or inverse agonist activities at a1, a2, and a3-subtype receptors. Doing some more research, it appears that the a1 subtype mostly modulates sedation, a2 and a3 modulate anxiety, and that a5 affects memory and cognition. Benzodiazepines apparently activate all four receptors, causing sedation, anxiolysis, and also some degree of acute and cumulative impairment of memory and cognition. Zolpidem is reasonably selective for a1, so it knocks you out without really relieving anxiety or messing with your brain. By contrast, α5IA is an inverse agonist at a5 and a very weak partial agonist at a2; it would thus appear that α5IA would have a very weak anxiolytic effect while boosting memory and cognition.
I did some more research and found a few mouse and human studies of the stuff. They tested it in mice with Down's syndrome, and found that daily 5mg/kg injections of α5IA for two weeks repaired basically all of the deficits in several immediate early genes associated with memorization (and thus helped the mice achieve much faster times through a standard water maze). Some basic human trials have been done for safety and nootropic efficacy, and the results were interesting. Apparently α5IA did nothing or worse for elderly people (tests showed that a 4mg dose actually worsened performance on a paired-associate learning task for elderly patients), but it basically undid cognitive impairment due to drunkenness in young, healthy volunteers. As far as I can tell, the big risk is that one of its metabolites has a solubility in water of around 600 ng/mL, which is high enough that dramatically increased doses of α5IA caused some degree of kidney damage which precluded long-term dosing regimes in subjects. It's also apparently well-tolerated in people up to at least 6mg in the short term, and it might turn out to be a really useful drug.
I was wondering if anyone on here either has personal experience with the stuff, or has better medical knowledge of what happens when you shut down GABA-A-a5. It's currently only available for $28 per milligram, but I poked a friend of a friend who's going to grad school for chemistry about the feasibility of a synthesis for it and would like opinions on whether it's worth the trouble