How does an agonist inhibit other agonists from binding to the same receptors that the other agonists are trying to bind to? (Valerian and LSD)

[Meremoth]

Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. ...

www.ncbi.nlm.nih.gov

In the article above it states:

"To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABAA receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT5a receptor, but only weak binding affinity to the 5-HT2b and the serotonin transporter. Subsequent binding studies focused on the 5-HT5a receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep–wake cycle. The PE extract inhibited [3H]lysergic acid diethylamide (LSD) binding to the human 5-HT5a receptor (86% at 50 μg/ml) and the DCM extract inhibited LSD binding by 51%."

How does valerian inhibit LSD from binding to the receptors that valerian agonizes (is agonizes the correct term?).

So agonists can inhibit other agonists from binding to the same receptors that both agonize? I thought that antagonists were the culprits that inhibit agonists, I didn't think agonists could inhibit other agonists from working in the same receptors

Can someone please explain this to me, I would very much appreciate it.

Thank you

 

[dopamimetic]

With two agents, depending on affinity but independent on potency (agonist - silent antagonist - inverse agonist), above a certain dose threshold they will compete for the binding site (why reuptake inhibitors block releasers). If they differ greatly in affinity, that one binding tighter will win (e.g. buprenorphine).

They radiolabel one ligand and measure its distribution, that's what is described. One agent can replace another of similar efficacy with no relevant changes in neurological activity but a very different distribution picture.

Interesting to read that valerian can displace LSD even when it's not 5ht2a. Valerian is weak as shit.

 

[Flower Fairy]

Interesting to read that valerian can displace LSD even when it's not 5ht2a. Valerian is weak as shit

I asked that very question about a month or so ago lol, I was using Promethazine and Valerian to come off Mirtazapine and have a blot of acid to try and asked if they'd block it like the Mirtazapine would

Well I'm back on Mirtazapine now but going to try and come off it again, now I know not to use Valerian lol

 

[polymath]

So agonists can inhibit other agonists from binding to the same receptors that both agonize? I thought that antagonists were the culprits that inhibit agonists, I didn't think agonists could inhibit other agonists from working in the same receptors

It does happen like that when both molecules bind to the same site of the receptor. It's no more complicated than an EDTA molecule displacing a less powerful chelating agent from a heavy metal ion. It looks more clear when you note that there isn't a clear-cut difference between an agonist and antagonist - there can be a full antagonist, 25% partial agonist, 50% partial agonist, full agonist, and anything between those.

 

[dopamimetic]

I asked that very question about a month or so ago lol, I was using Promethazine and Valerian to come off Mirtazapine and have a blot of acid to try and asked if they'd block it like the Mirtazapine would

Well I'm back on Mirtazapine now but going to try and come off it again, now I know not to use Valerian lol

Umm it depends on the effects and receptors. The primary effects of psychedelics are mediated over the 5ht2a receptor but others contribute to the overall profile, like the infamous 5ht2b (causes heart valve damage with prolonged overactivation - serotonin has very different effects outside the CNS, that's why it's called sero-ton(e)-in but the same receptor inside the CNS mediates part of the empathogenic experience).

Both valerian and LSD are agonists at the 5ht5a site, as is the antipsych olanzapine, so I don't expect valerian to be relevant here.

Mirtazapine is a 5ht2a antagonist tho.

 

[polymath]

When those valerian-type mild benzodiazepine-like substances are tested for GABA-A binding, it's done by measuring how they displace a radiolabelled flunitrazepam molecule from the GABA-A receptor. It's exactly the same situation as with the 5-HT2A binding.