Group items tagged

The prospect that drugs might be able to enhance one or more modalities of cognition has garnered a great deal of attention in the past few years, nowhere more so than among neuroethicists.  Much of the discussion revolves around existing drugs such as methylphenidate, but the truth is that the effects they produce are measurable but modest, and in my view the current situation is not as dire as some might suggest. That might not be the case in the future, especially once ‘real’ pharmacological cognitive enhancers are developed.  To date, the results have been disappointing.  [Warning: the rest of this post is weighted more towards science than neuroethics.] The development of ampakines by Cortex Pharmaceuticals looked promising at first, with preliminary results suggesting that these compounds might improve at least some aspects of memory in humans, but then the drugs failed to reach their end point in Phase II clinical trials.  A great deal of excitement emerged from the idea that one might be able to enhance the activity of the transcription factor CREB, primarily by inhibiting the enzyme phosphodiesterase-4 (PDE4) which is responsible for breakdown of cAMP.  If successful, the increase in CREB activity was hypothesized to enhance long-term memory.  The prominent players in PDE4 development for cognitive enhancement to date have been Memory Pharmaceuticals and Helicon Pharmaceuticals;  both companies developed drugs which advanced to Phase II testing for age-associated memory impairment, but neither drug met the requisite endpoint at moderate doses, and at higher doses ran into troublesome side effects such as nausea which have begun to be seen as a general problem with PDE4 inhibitors. But a good idea does not lay fallow long, and a new report in Nature Biotechnology from Alex Burgin and colleagues at deCODE biostructures opens up a new era in the pursuit of PDE4 inhibitors for cognitive enhancement.  The paper is a tour de force of structural biology and medicinal chemistry.  Essentially, Burgin et al. noticed that all previous attempts to develop PDE4 inhibitors were based on developing competitive inhibitors.  Reasoning that these compounds may have been more hammer than scalpel, they used insights from their crystallography work to design allosteric modulators which might allow better titration of the cAMP signal and presumably allow fine tuning of CREB activity.  Using this strategy they ultimately came up with 140 compounds that satisfied their criteria; the most promising of these were then demonstrated to the desired effects upon long-term memory and have many of the characteristics one might wish for in a bona fide cognitive enhancer.