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Figure 14.3
Structures of rapamycin analogs currently approved for human use or in
clinical trials: temsirolimus, everolimus, zotarolimus, and ridaforolimus.
chicken dorsal root ganglia (DRG) explants, rat DRGs, and in a sciatic nerve
injury model.
51
It has also been proposed that neuroprotection is mediated by
immunophilins other than FKBP12, notably FKBP52 and FKBP38.
24,48
When
we started our efforts, attempts to develop therapeutically useful compounds by
uncoupling neuroprotection from immunosuppression in this class of com-
pounds had met with limited success.
51
We undertook a focused initiative to identify new, neuroprotective natural
product immunophilin ligands based on multiple hypotheses: (i) that FKBP
binding alone cannot account for the mechanism of neuroprotection; (ii) that
the marginal neuroprotective effects of rapamycin, in contrast to FK506,
suggest that mTOR binding is not required for this activity; and (iii) that
therefore compounds with FKBP binding domains and modified ''effector''
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