Will There Ever Be An SR-17018 for B3nz0s?

bluemannn said:

I know SR is a miracle drvg for 0p1ates,

but Will there ever be an "SR" for b3nz0s?
That would be a literal Godsend considering the h3ll that is b3nz0 WD.

Thx

Click to expand...

Shotta609 said:

What exactly is that SR?

Click to expand...

bluemannn said:

I know SR is a miracle drvg for 0p1ates,

but Will there ever be an "SR" for b3nz0s?
That would be a literal Godsend considering the h3ll that is b3nz0 WD.

Thx

Click to expand...

baberuth said:

I guess it depends on exactly what you mean by "an SR-17018 for benzos," but, in short, I'd guess no. I'm not a biochemist so don't quote me here, but this is why I say no:

The subjective effects of mu opioid agonists are sundry, and some of these effects are linked to different pathways of mu opioid agonism. SR-17018 preferentially stimulates G protein signaling pathways. (The mu opioid receptor is a G protein coupled receptor or GCPR.) In GCPRs, agonism induces a cascade of intracellular effects - essentially a growing chain reaction (more or less) that leads to the ultimate results you feel. What's different about SR-17018? It achieves what was just described while largely ignoring beta-arrestin recruitment. Beta-arrestin is involved in desensitization to GCPR agonism and receptor internalization, among other things. This is presumably why SR-17018 yields some opioid effects (namely analgesia) without others (notably euphoria and the accruing of tolerance, at least relative to traditional opioids).

The GABA A receptor that benzos bind is a ligand-gated ion channel, not a GCPR, so things just work differently. In my head at least, it's just a simpler system. Rather than having an extracellular ligand cause a growing cascade of intracellular effects which then interact with one another, mostly via positive feedback loops but in unique ways (as GCPRs do), a ligand-gated ion channel is basically just a pore that opens to permit something to enter or exit the cell when bound by a ligand. Now once again, things can happen inside the cell that make it more complicated than that, but that's more of an afterthought for ligand-gated ion channels while, for GCPRs, it's the whole point of agonism.

Maybe worth mentioning that benzos are NOT the endogenous ligand at GABA A (probably obvious). That would be GABA, which shocker. Benzos bind allosterically, meaning at a separate site than the "usual" endogenous ligand, and then, once GABA (the neurotransmitter, not the receptor) comes along, the GABA A receptor will respond differently to GABA binding it when benzos are present than when they are not. So maybe a better understanding of allosteric modulation at GABA A could help us pare down the negative effects of benzos while retaining the positives, but as far as creating a drug that achieves what benzos do without accruing significant tolerance... I do not see how that would work. But I could be wrong!

Click to expand...

baberuth said:

I guess it depends on exactly what you mean by "an SR-17018 for benzos," but, in short, I'd guess no. I'm not a biochemist so don't quote me here, but this is why I say no:

The subjective effects of mu opioid agonists are sundry, and some of these effects are linked to different pathways of mu opioid agonism. SR-17018 preferentially stimulates G protein signaling pathways. (The mu opioid receptor is a G protein coupled receptor or GCPR.) In GCPRs, agonism induces a cascade of intracellular effects - essentially a growing chain reaction (more or less) that leads to the ultimate results you feel. What's different about SR-17018? It achieves what was just described while largely ignoring beta-arrestin recruitment. Beta-arrestin is involved in desensitization to GCPR agonism and receptor internalization, among other things. This is presumably why SR-17018 yields some opioid effects (namely analgesia) without others (notably euphoria and the accruing of tolerance, at least relative to traditional opioids).

The GABA A receptor that benzos bind is a ligand-gated ion channel, not a GCPR, so things just work differently. In my head at least, it's just a simpler system. Rather than having an extracellular ligand cause a growing cascade of intracellular effects which then interact with one another, mostly via positive feedback loops but in unique ways (as GCPRs do), a ligand-gated ion channel is basically just a pore that opens to permit something to enter or exit the cell when bound by a ligand. Now once again, things can happen inside the cell that make it more complicated than that, but that's more of an afterthought for ligand-gated ion channels while, for GCPRs, it's the whole point of agonism.

Maybe worth mentioning that benzos are NOT the endogenous ligand at GABA A (probably obvious). That would be GABA, which shocker. Benzos bind allosterically, meaning at a separate site than the "usual" endogenous ligand, and then, once GABA (the neurotransmitter, not the receptor) comes along, the GABA A receptor will respond differently to GABA binding it when benzos are present than when they are not. So maybe a better understanding of allosteric modulation at GABA A could help us pare down the negative effects of benzos while retaining the positives, but as far as creating a drug that achieves what benzos do without accruing significant tolerance... I do not see how that would work. But I could be wrong!

Click to expand...

Cal1lab said:

You know more about drugs than me and that doesn’t happen often

Click to expand...