Bay 60-7550

Bay 60-7550 is a potent and selective inhibitor of 3’,5’-cyclic nucleotide phosphodiesterase type 2 (PDE2) with IC50 value of 4.7 nM for human recombinant PDE2 [1].
In the signal transduction process, the redundant second messenger cGMP is degraded by the cyclic nucleotide phosphodiesterases. Among the 11 families of PDEs, PDE2 can hydrolyse both cAMP and cGMP and control the levels of both them in the areas which are important for memory formation and storage. Therefore, the inhibition of PDE2 activity is thought to be good to improve memory functions via enhancing neuronal plasticity. Bay 60-7550 is a highly potent and selective inhibitor of PDE2. It increased the levels of cGMP in both hippocampal slices and cultured neurons. In animal models, Bay 60-7550 was found to have positive effects on there cognition performance [1].
As a potent PDE2 inhibitor, Bay 60-7550 suppressed activity of the purified enzyme obtained from bovine heart with an IC50 value of 2 nM. It showed no significant effects on other PDEs including PDE1, 3B, 4B, 5, 7B, 8A, 9A, 10A and 11A. For other similar receptors or enzymes, the IC50 values of Bay 60-7550were all more than 10 μM. Besides that, Bay 60-7550 had no effects on adenosine deaminase even though the concentration was up to 10 μM. In cultured rat cortical neurons and hippocampal neurons, the combination therapy of Bay 60-7550 and Bay 41-8543 resulted in notably increase of cGMP levels. In rat hippocampal slices, treatment of Bay 60-7550 caused a significant higher potentiation of the field excitatory postsynaptic potential slope [1].
In rodent models, oral administration of Bay 60-7550 at doses of 1 and 3 mg/kg resulted in improvement of memory performance. In addition, Bay 60-7550 was found to mediate decrease of oxidative stress in mice models. It significantly reversed the decrease of both percentage of open arm entries and percentage of open arm time induced by oxidative stress at dose of 3 mg/kg in the elevated plus-maze test [1 and 2].
References:
[1] Boess FG, Hendrix M, van der Staay FJ, Erb C, Schreiber R, van Staveren W, de Vente J, Prickaerts J, Blokland A, Koenig G. Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance. Neuropharmacology. 2004 Dec;47(7):1081-92.
[2] Masood A, Nadeem A, Mustafa SJ, O'Donnell JM. Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice. J Pharmacol Exp Ther. 2008 Aug;326(2):369-79.

The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity.[Pubmed:27813297]

Eur J Neurosci. 2017 Feb;45(4):510-520.

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. Bay 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of Bay 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of Bay 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with Bay 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, Bay 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.