What makes a molecule active ?

[Lightning-Nl]

Totally agreed Atara...First a psychoactive compund has to alter neural signaling (trough enzymes or act directly to neurons receptors as being similar compounds to neurotransmitters) and also must be lipophilic enough to get trough Blood Brain Barier.

As sekio said above, a compound doesn't have to a certain degree of lipophilicness or hydrophilicness in order to cross the blood-brain barrier.

Also, the compound doesn't have to modulate the natural neuronal signaling - there are some substances that actually mimic the neuronal signals themselves. So that means these substances mimic sodium, potassium, calcium, and chloride cations. Blockers of these channels, work in a similar way, although, they don't actually mimic electronic impulses or change the charge of one side of the neuron.

They work by literally blocking the ions from being able to get through the channel, by (as the name suggests). They do this by blocking that channel with their "body". So no matter what the electrical charge of one side of the cell is - the ions can't get through (even if they "want" to).

This causes decreased firing of neurons as the electronic impulses that would carry the signal - aren't getting through to carry that message. This, in turn, alters your state of mind.

 

[ebola?]

As sekio said above, a compound doesn't have to a certain degree of lipophilicness or hydrophilicness in order to cross the blood-brain barrier.

It's very atypical for compounds that aren't remotely lipophilic to penetrate the BBB.

there are some substances that actually mimic the neuronal signals themselves.

An action potential (the neural signal as it propagates down the axon) is an event, where the depolarization of differential charge across a membrane propagates. It isn't correct to say that a substance can mimic it.

This causes decreased firing of neurons as the electronic impulses that would carry the signal - aren't getting through to carry that message.

It can also increase the propensity of action potentials to propagate, depending on which ion is being blocked.

ebola

 

[Hammilton]

That chart made me genuinely laugh out loud. Priceless. These three extra hydrogens... how many are connected to the methyl carbon? Both methyl carbons, that is. Counting the one on the amine, I count seven hydrogen atoms. Well, eight if I count the alpha carbons.

 

[Lightning-Nl]

That chart made me genuinely laugh out loud. Priceless. These three extra hydrogens... how many are connected to the methyl carbon? Both methyl carbons, that is. Counting the one on the amine, I count seven hydrogen atoms. Well, eight if I count the alpha carbons.

Oh hammilton....

How you never fail to lighten up my day You just reminded me of our argument about BZD's, stimulant combinations, etc... So I thought I'd drop this here

My claim was that; an agonist is a substance that can bind to a receptor and induce a response from that neuron, without any other substance interacting with it. I then proceeded to say that since a benzo can't induce a response from the neuron, without GABA being present, it's, therefore, not an agonist.

That's correct, benzodiazepines are not agonists at GABA-a - the technical term is a "positive allosteric* modulator". They only increase the frequency and duration of GABA-a activation.

I'm sure Sekio wouldn't have a problem with explaining to you why you were wrong.

 

[ebola?]

Eh...this is a simple semantic disagreement over whether the term "agonist" should include indirect agonists or not; I don't see how the point could matter.

ebola

 

[Lightning-Nl]

Eh...this is a simple semantic disagreement over whether the term "agonist" should include indirect agonists or not; I don't see how the point could matter.

ebola

My understanding of the term "indirect agonist" would be a substance that causes agonization of a receptor - without that chemical having any binding affinity for that receptor. Since that's the case, that means the indirectly agonizing substances has to induce a response a different way. A good example of this how nAChR's function in the autonomic nervous system.

Nicotinic Acetylcholine agonism is entirely excitatory in ANS. But the actual increase in heart beat, faster breathing, etc. isn't actually caused by the cholinergic agonist. When the substance agonizes nAChR, the response to the neuron is excitatory - and to cause stimulation of other neurons - the ACh Neuron releases Norepinephrine. This causes stimulation of other neurons, causes inhibition of inhibitor neurons, and therefore - your heart beat increases.

This makes ACh (when it binds to nAChR), in the ANS, an indirect agonist of Norepinephrine. To relate this to Benzodiazepines - benzodiazepines don't cause a release of another neurotransmitter. They increase the firing of the chloride channel, and therefore, make excitatory neurons less excitable, and inhibitory neurons more excitable - but this can't be achieved without some sort of substance inducing that response in the first place. Therefore, it's questionable whether or not BZD's should even be considered indirect agonists

It also appears to me that the term, indirect agonist, could therefore be synonymous with the term "releasing agent". But that's another subject.

Since allosteric modulators aren't releasing agents of GABA (in the case of benzodiazepines, barbiturates, ethanol, and nonbenzodiazepines, that is) it seems appropriate to me that even indirect agonist wouldn't apply to these substances since, again, they aren't inducing a response without the "help" another chemical being present. And the response they are inducing, isn't agonism, but rather "longer duration of firing"

 

[sekio]

Swampfox, you are confusing indirect agonism with downstream activity in your example about ACh, I think. Because ACh does not increase norepinrphrine release everywhere in the body, it is not considered an indirect agonist because... it isn't, in all situations. A more apt example of "indirect agonism" is the blockade of dopamine transporters causing an elevation in postsynaptic dopamine, ergo acting, indirectly, as an agonist. Or a drug that blocks the metabolic breakdown of synaptic dopamine, like a MAOI.

And the response they are inducing, isn't agonism, but rather "longer duration of firing"

... which in this case is considered agonism.

This is all just semantic nit picking.

 

[ebola?]

My understanding of the term "indirect agonist" would be a substance that causes agonization of a receptor - without that chemical having any binding affinity for that receptor.

This is actually slightly more specific than a proper generalized definition of the term. We can say that an indirect agonist causes a subsequent change in cellular activity resembling that of direct agonism without directly binding to the receptor as the endogenous neurotransmitter would. Thus, the augmentation of the endogenous ligand's effect exerted by positive allosteric modulators falls within the umbrella of indirect agonism.

edited to add: I think that sekio's point about how far this description should extend stands: it would cause explanations to become profoundly incoherent if vastly downstream effects where considered "indirect agonism", opening the door to everything being an indirect agonist everywhere.

ebola