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Magic softballs versus magic shotguns?

I read with great interest the thoughtful article by Roth et al.1 on the strategies that might have to be applied in order to yield new drugs for mood disorders and schizophrenia. I have one general comment that might go beyond these indications and could be interesting in general for drugs acting on the nervous system. It seems to me that the best — in the sense of having the highest benefit/risk ratio — drugs in many fields are the ones with a low affinity (examples are given in Table 1). When looking in more detail at their affinity constants (Kd = k−1/k+1), it seems that these drugs are characterized by a relatively fast off-rate (k−1) from their target (receptor or ion channel), whereas their on-rate is similar to the that of drugs (or toxins) with more side effects related to their pharmacological action. As discussed by others (for example, Refs 2,3), this might be advantageous for different reasons. In the field of dopamine D2 antagonists, a fast off-rate will allow dopamine to act normally in the nigro-striatal system, especially when it is released in large amounts that are able to displace rapidly the antagonist. This might allow the avoidance of extrapyramidal side effects (although I agree that the action of these drugs on other receptors might also contribute to the low incidence of extrapyramidal side effects).

Table 1 Drugs with low affinity

In the field of Na+ channel blockers, a fast off-rate might help to decrease, with some selectivity, the firing rate of hyperactive neurons versus normal neurons (in the case of antiepileptic drugs) and to avoid a build up of Na+ channel blockade in the heart (in the case of the local anaesthetics). More conceptually (but this is very hypothetical), it might turn out that the disruption of a biological system, even when it is in part pathological, should be mild or short-lived in order to maintain some kind of homeostasis. Another example is provided by gabapentin, which can also be considered as a mild disrupter of neurotransmission by acting (again with a low affinity) on an accessory subunit of Ca2+ channels.

Whatever the explanation, I believe that this possibility — that less affinity with a fast off-rate might be better — should be borne in mind by scientists involved in drug design.

References

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Seutin, V. Magic softballs versus magic shotguns?. Nat Rev Drug Discov 3, 894 (2004). https://doi.org/10.1038/nrd1346-c1

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