The authors of this article [Stott et al., 1996: (http://cat.inist.fr/?aModele=afficheN&cpsidt=3197621)] discuss research showing that the pKa values for the secondary amine nitrogens of doxepin, amitriptyline, and imipramine range from 9.0 to 9.4. The tricyclics' uncoupling effects, to the extent that they may occur in vivo (http://hardcorephysiologyfun.blogspot.com/2009/07/mild-uncoupling-as-factor-that-may.html), may be at least partially a result of the tricyclics' being lipophilic weak bases and also roughly planar, etc. Some uncouplers are lipophilic, weak bases with pKa values in that range (others are weak acids) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pKa+mitochondrial+uncoupling+%22weak+base%22+OR+%22weak+acid%22); (http://hardcorephysiologyfun.blogspot.com/2009/05/some-structure-activity-relationships.html)]. For example, Garlid et al. (1983) [Garlid et al., 1983: (http://www.jbc.org/cgi/reprint/258/13/7974.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6223029)] noted that lipophilic amines can produce uncoupling and mimick the effects of weak acid uncouplers (Garlid et al., 1983). Some lipophilic amines, as Garlid et al. (1983) discuss, can produce uncoupling by interacting with anions in "ion pairs." It's interesting that Garlid et al. (1983) found some uncoupling effects from quinidine, because tricyclics, especially at higher or toxic doses, produce quinidine-like cardiotoxicity, partly as a result of their anticholinergic effects, and thereby produce QT-interval prolongation and hence produce quinidine-like anti-arrhythmic effects [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=quinidine+tricyclic); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=quinidine+tricyclic+antiarrhythmic)]. Garlid et al. (1983) also tested some other drugs, such as chlorpromazine, used in psychiatry, and some local anesthetics. Some of those anesthetics have overlapping pharmacological mechanisms with tricyclics (sodium-channel blocking effects), but that could just mean that the different drugs are lipophilic amines and weak bases. But there does tend to be a structural requirement, such as a bulky, aromatic substituent, for a drug to produce uncoupling. It's not enough that it's a weak base. Its half-life, for example, would be one determinant. I think tacrine accumulates, for example, over time, more than many drugs (the authors discuss that in the article I cited in the previous posting (http://hardcorephysiologyfun.blogspot.com/2009/07/mild-uncoupling-as-factor-that-may.html).
The "bulky," heterocyclic ring system probably would play a role in any supposed uncoupling effects, also, but I'm not sure what the role would be. One might ask why not all antidepressants are weak acids or weak bases and why not all of them produce uncoupling, etc. I'm not trying to explain antidepressant actions in general. This is just one factor that seems like it might be relevant and might be one effect of some antidepressants. Obviously, there would be potential for harm from uncoupling, but the point is that the induction of mild uncoupling by some of these approaches (even exercise may have some of those effects in astrocyte mitochondria) could be viewed as being a bioenergetic compromise of some kind. Another possibility is that the wastefulness of it, the ATP depletion, could cause an adaptive change in glycogen storage, etc.
It's interesting that reserpine (a plant-based drug that depletes vesicular stores of monoamine neurotransmitters, by blocking their uptake into vesicles by vesicular monoamine transporters, and is basically the opposite of an antidepressant) produces uncoupling (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=uncoupling+mitochondria+psychiatric+OR+psychoactive+OR+antidepressant), and that could either cast serious doubt on this concept or could indicate that severe uncoupling produces severe ATP depletion that the stimulation of respiration, in response to the uncoupler, can't compensate for. In any case, I still think it's interesting that chlorpromazine was the strongest uncoupler in some of the experiments that Garlid et al. (1983) conducted, and that might suggest that there can be a spectrum of effects. Milder uncouplers might stimulate respiration enough to more than compensate for the initial ATP depletion, produced as a result of the futile cycling that the uncoupler causes. Stronger uncouplers might produce more significant ATP depletion and "tranquilizing" or toxic effects, etc.
In any case, those are interesting articles, but these are just inchoate thoughts. It's interesting to think about that type of thing.
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