The cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction and selective inhibitors of the different subtypes have great clinical potential. PDE4 inhibitors are expected to be beneficial in the treatment of inflammatory and respiratory diseases such as asthma and COPD as well as CNS disorders including schizophrenia, depression, and Alzheimer’s disease but their potential has so far been limited by the incidence of side effects, particularly emesis. The emetic response is mediated in part by a brainstem noradrenergic pathway and, for non-CNS indications, can be reduced by limiting distribution of inhibitors to the brain. Active site directed PDE4 inhibitors completely inhibit enzyme activity at high concentrations but researchers at Emerald Biostructures (formerly deCODE biostructures) have now identified allosteric small molecule modulators of PDE4 with reduced potential for side effects. The four PDE4 variants (PDE4A, B, C, and D) all contain signature regulatory domains called upstream conserved regions 1 and 2 (UCR1 and UCR2). UCR2 is needed for high-affinity binding of the PDE4 inhibitor rolipram and X-ray crystallographic structures revealed that small molecule inhibitors bind to UCR2, thereby controlling access to the active site. The team used the structural data together with supporting mutational data to design PDE4 allosteric modulators that only partially inhibit cAMP hydrolysis. The modulators were shown to be potent in cellular assays as well as in vivo cognition tests and to have greatly reduced potential for emesis in several species. The authors hope that their work will lead to the identification of PDE4 modulators with reduced potential for emesis that can be used to treat disorders where brain distribution is needed. The study is published in the December 27th advance online issue of Nature Biotechnology.