Small Molecule Allosteric Modulators of Phosphodiesterase 4 - Phosphodiesterases as Drug Targets - page 182

in the active site (Huston et al. 1996 ). Imaging of cAMP concentrations in cortical
neurons using biosensors also suggests that submembrane and cytosolic cAMP
microdomains are affected differently by rolipram (Castro et al. 2010 ). Rolipram
affects free cAMP more strongly in the apical dendrites of parietal cortex neurons
as compared to the bulk cytosol. The basis for these differences between cytosolic
and membrane-bound forms of PDE4 is not understood, but could include an effect
of interacting proteins on UCR2 gating or on PDE4 dimer formation.
Recently, we have shown that PDE4D selective allosteric modulators have
similar efficacy and slightly greater potency than rolipram in tests of short- and
long-term memory, Table 4 (Burgin et al. 2010 ). Before the interest in the use of
PDE4 inhibitors for treating anti-inflammatory conditions, the prototypical PDE4
selective inhibitor, rolipram, was explored in animal models and human clinical
trials for the treatment of depression (Wachtel 1983 ; Zeller et al. 1984 ; Bobon
et al. 1988 ; Laux et al. 1988 ; Hebenstreit et al. 1989 ; Scott et al. 1991 ; Fleisch-
hacker et al. 1992 ). However, the nausea/emesis side-effect profile led to a cessa-
tion of interest in this. Interestingly, there recently has been a resurgence of interest
in this use for PDE4 inhibitors, which have again now entered clinical development
to treat depression and improve cognition (Tully et al. 2003 ). With regard to the
antidepressant effect in animal models, PDE4 inhibitors have immediate effects on
behavior (Zhang et al. 2006 ) as well as long-term effects on growth factor expres-
sion in brain (Fujimaki et al. 2000 ) and hippocampal neurogenesis (Li et al. 2009 ).
Indeed, rolipram has benefit in multiple animal models of short- and long-term
memory formation (Blokland et al. 2006 ), enhances long-term potentiation of
synaptic efficacy (Vecsey et al. 2009 ), and is protective in transgenic models
of Alzheimer's disease (Gong et al. 2004 ; Smith et al. 2009 ) and Huntington's
disease (DeMarch 2008 ). PDE4 modulates cAMP-dependent phosphorylation of
the CREB transcription factor, a pathway critical for long-term memory formation

Table 4 Procognitive benefit of rolipram and a PDE4D selective, allosteric modulator in com-
parison to emetic dose in Suncus murinus (Asian house shrew), the beagle dog, and cynomolgus
monkey
Procognitive benefit in mice
Test Rolipram MED (mg/kg) D159687 MED (mg/kg)

Scopolamine impaired Y-maze 0.03 0.01

Novel object recognition after 24 h 0.10 0.03

Emetic threshold
Species Rolipram NOEL (mg/kg) D159687 NOEL (mg/kg)
Suncus murinus 0.10 10
Beagle dog 0.10 300
Cynomolgus monkey 0.02 10
Compounds were dosed orally. The minimum effective dose (MED) for procognitive benefit was
the lowest dose at which discrimination in the Y-maze or NOR test was statistically significant
(Burgin et al. 2010 ). The No Observable Effect Level (NOEL) for emesis was the maximum dose
at which no effect on emesis was observed. Rolipram data in Suncus are from (Hirose et al. 2007 ),
rolipram data in dog are from (Heaslip and Evans 1995 ), and the rolipram emetic threshold in the
cynomolgus monkey is projected based on allometric scaling from human (Hebenstreit et al. 1989 )