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Re: To SLS - clorgyline and imidazoline

Posted by undopaminergic on January 3, 2020, at 10:35:17

In reply to To SLS - clorgyline and imidazoline, posted by linkadge on January 2, 2020, at 15:52:40

> I recall you once saying that you had a good response to the drug clorgyline. I was reading about it on Wikipedia and apparently (in addition to being a potent MAOI)

To be precise, it is a selective irreversible inhibitor of MAO-A. You need to follow the MAOI diet with it because the MAO in the gut is of the A isoform.

> it is an even more potent agonist at the imidazoline receptors (in the PICOMOLAR concentration):

The article also says it has very high (nanomolar) affinity for the sigma1-receptor, but doesn't specify whether it is an agonist or antagonist. Anyway, this action is probably of significance.

> Imidazoline receptors have been studied in depression and may have some antidepressant effect.

There are three known subtypes of the imidazoline receptor. Agonism at the I1-subtype has been associated with hypotensive effects. Clonidine is a mixed I1-receptor and alpha2A-adrenoceptor agonist.
<<Imidazoline receptors are the primary receptors on which clonidine and other imidazolines act. There are three main classes of imidazoline receptor: I1 is involved in inhibition of the sympathetic nervous system to lower blood pressure, I2 has as yet uncertain functions but is implicated in several psychiatric conditions, and I3 regulates insulin secretion.>>

and: <<Nonselective ligands:
* Agmatine (putative endogenous ligand at I1; also interacts with NMDA, nicotinic, and alpha2 adrenoceptors)
* Apraclonidine (alpha2 adrenoceptor agonist)
* Cimetidine (I1 agonist, H2 receptor antagonist)
* Clonidine (I1 agonist, alpha2 adrenoceptor agonist)
* Dimethyltryptamine
* mCPP
* Moxonidine
* Oxymetazoline (I1 agonist, alpha1 adrenoceptor agonist, alpha2 partial agonist)
* Rilmenidine
* Tizanidine
<<... It acts as both a selective alpha2 adrenergic receptor antagonist, and an antagonist for the imidazoline receptor. Idazoxan has been under investigation as an antidepressant, ... it is under investigation as an adjunctive treatment in schizophrenia. Due to its alpha-2 receptor antagonism it is capable of enhancing therapeutic effects of antipsychotics, possibly by enhancing dopamine neurotransmission in the prefrontal cortex of the brain, ...>>

> I believe agmatine (a cheap supplement with purported antidepressant effect) is also an imidazoline agonist.

It is.
<<Mechanisms of action: Agmatine was found to exert modulatory actions directly and indirectly at multiple key molecular targets ...:
* Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, alpha2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors.
* Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).
* Nitric oxide (NO) synthesis modulation. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.
* NADPH oxidase. Activation of the enzyme leading to H2O2 production.

and: <<Research -- Neurotransmission: Agmatine has been discussed as a putative neurotransmitter. It is synthesized in the brain, stored in synaptic vesicles, accumulated by uptake, released by membrane depolarization, and inactivated by agmatinase. Agmatine binds to alpha2-adrenergic receptor and imidazoline receptor binding sites, and blocks NMDA receptors and other cation ligand-gated channels. Short only of identifying specific ("own") post-synaptic receptors, agmatine in fact, fulfills Henry Dale's criteria for a neurotransmitter and is hence, considered a neuromodulator and co-transmitter. ...>>

and: <<Research -- Opioid liability: Systemic agmatine can potentiate opioid analgesia and prevent tolerance to chronic morphine in laboratory rodents. Since then, cumulative evidence amply shows that agmatine inhibits opioid dependence and relapse in several animal species.>>

> I wondered if you considered adding agmatine to your current regiment? (with or without a MAOI).

Seems to me that an exciting combination could be morphine (or other opioid) + agmatine.





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