HUH...subbing so strongly for LSD I am not sure where he gets the idea of thinking plausibility for related compounds to engage treatment for cognitive disorders...???!!!!
We emphasize the fact that 2 is a functionally selective
agonist at the 5-HT2A receptor, having about 65-fold selectivity
for the activation of the PLC signaling pathway over arachidonic
acid release or 2-arachidonylglycerol (2-AG) production (Table
2). Although it is generally assumed that all 5-HT2A agonists
will possess hallucinogenic properties, a belief that has led to
their neglect by the pharmaceutical industry, we challenge that
assumption. We have previously shown that hallucinogenic
activity is better correlated with production of arachidonic acid
than with activation of PLC.16 If hallucinogenic properties are
in fact associated with the production of arachidonic acid, or
other eicosanoids, and not phosphoinositide turnover, it seems
entirely possible that functionally selective 5-HT2A agonists such
as 2 might represent new therapies. In particular, on the basis
of the high expression of 5-HT2A receptors on cortical pyramidal
cells, where agonists at this receptor depolarize the cell
membrane (see review by Nichols12), one could speculate that
functionally selective 5-HT2A agonists might be useful in treating
cognitive and memory deficits.
Thus, the present results are important not only because they
identify the binding orientation of agonists at this receptor but
because they also potentially provide a lead compound for
discovery of novel therapies for various types of cognitive
dysfunction. Finally, these results also provide a compelling case
for conformational restriction as a powerful tool for the design
of functionally selective analogues from nonselective flexible
agonists.
.