Related Experiment Video
Updated: Jul 14, 2026
08:52
Novel Object Recognition Test for the Investigation of Learning and Memory in Mice
Published on: August 30, 2017
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties
Brian Dyck1, Bryan Branstetter1, Tawfik Gharbaoui1
1Dart Neuroscience LLC , 12278 Scripps Summit Drive, San Diego, California 92131, United States.
Journal of Medicinal Chemistry
|April 14, 2017
Summary
Researchers discovered new PDE1 inhibitors for potential memory enhancement. One compound showed oral bioavailability and brain penetration, improving memory in rats by inhibiting PDE1B.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Enzyme Inhibition
Background:
- Phosphodiesterase 1 (PDE1) enzymes play a role in cognitive function.
- Developing selective PDE1 inhibitors is a therapeutic strategy for cognitive disorders.
Purpose of the Study:
- To discover and optimize novel thienotriazolopyrimidinone-based inhibitors of PDE1.
- To evaluate the in vivo efficacy of a lead compound for memory enhancement.
Main Methods:
- Synthesis and characterization of thienotriazolopyrimidinone derivatives.
- X-ray crystallography to determine compound-enzyme complexes with PDE1B and PDE10A.
- In vitro assays for enzyme inhibition and selectivity (PDE1B vs. hERG).
- In vivo testing in a rat model of object recognition memory.
Main Results:
- Discovery of potent thienotriazolopyrimidinone-based PDE1 inhibitors.
- Structural elucidation of inhibitor complexes with PDE1B and PDE10A.
- Identification of a compound with >3000-fold selectivity for PDE1B over hERG.
- Demonstration of oral bioavailability, brain penetration, and memory-enhancing effects in rats.
Conclusions:
- The identified thienotriazolopyrimidinone derivative is a promising PDE1B inhibitor.
- This compound exhibits potential as a therapeutic agent for cognitive impairment.
- Further development could lead to treatments for memory-related disorders.
More Related Videos
Related Concept Videos
01:35Long-term Potentiation
Long-term potentiation, or LTP, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTP is the process of synaptic strengthening that occurs over time between pre- and postsynaptic neuronal connections. The synaptic strengthening of LTP works in opposition to the synaptic weakening of long-term depression (LTD) and together are the main mechanisms that underlie learning and memory.
01:25Long-term Potentiation
Long-term potentiation, or LTP, is one of the ways by which synaptic plasticity—changes in the strength of chemical synapses—can occur in the brain. LTP is the process of synaptic strengthening that occurs over time between pre and postsynaptic neuronal connections. The synaptic strengthening of LTP works in opposition to the synaptic weakening of long-term depression (LTD) and together are the main mechanisms that underlie learning and memory.
Hebbian LTP
LTP can occur when presynaptic neurons...
Hebbian LTP
LTP can occur when presynaptic neurons...
01:25Adrenergic Agonists: Indirect-Acting Agents
Indirect-acting adrenergic agonists potentiate the effects of endogenous catecholamines through different mechanisms without directly binding to adrenoceptors.
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
One mechanism involves depleting stored catecholamines by displacing them from synaptic vesicles. These agents, known as "displacers," are transported into vesicles at the expense of noradrenaline. Examples include amphetamine and tyramine, which lack a catechol moiety, resulting in prolonged action, improved oral bioavailability, and...
01:30Cognitive Enhancers: Cholinesterase Inhibitors and NMDA Receptor Antagonists
Cognitive enhancers, also known as "smart drugs," are substances used to enhance memory, mental alertness, and concentration. These can be natural or synthetic and improve cognition in conditions like Alzheimer's disease (AD) and other neurodegenerative diseases. Some common examples include caffeine, amphetamines, methylphenidate, modafinil, arecoline, donepezil, vortioxetine, and piracetam. These enhancers work on the principle of synaptic plasticity and altered circuit function. They...
01:22Alzheimer's Disease: Treatment
Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
01:28Treatment for Pulmonary Arterial Hypertension: Phosphodiesterase Inhibitors
Phosphodiesterase 5 (PDE5) inhibitors are potent enzymes that function to hydrolyze cyclic nucleotides to their corresponding 5' monophosphates. Their unique biochemical properties have been applied in treating Pulmonary Arterial Hypertension (PAH).
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...
Among the PDE5 inhibitors, sildenafil (Revatio) stands out as a competitive and selective inhibitor. It operates by elevating cellular levels of cGMP and augmenting signaling through the cGMP-PKG pathway, promoting vasodilation. Upon oral...