Therapeutic targeting of 3’,5’-cyclic nucleotide phosphodiesterases: inhibition and beyond

Phosphodiesterases (PDEs), enzymes that degrade 3′,5′-cyclic nucleotides, are being pursued as therapeutic targets for several diseases, including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Clinical development programmes have focused exclusively on catalytic inhibition, which continues to be a strong focus of ongoing drug discovery efforts. However, emerging evidence supports novel strategies to therapeutically target PDE function, including enhancing catalytic activity, normalizing altered compartmentalization and modulating post-translational modifications, as well as the potential use of PDEs as disease biomarkers. Importantly, a more refined appreciation of the intramolecular mechanisms regulating PDE function and trafficking is emerging, making these pioneering drug discovery efforts tractable

Therapeutic targeting of 3’,5’-cyclic nucleotide phosphodiesterases: inhibition and beyond

Phosphodiesterases (PDEs), enzymes that degrade 3′,5′-cyclic nucleotides, are being pursued as therapeutic targets for several diseases, including those affecting the nervous system, the cardiovascular system, fertility, immunity, cancer and metabolism. Clinical development programmes have focused exclusively on catalytic inhibition, which continues to be a strong focus of ongoing drug discovery efforts. However, emerging evidence supports novel strategies to therapeutically target PDE function, including enhancing catalytic activity, normalizing altered compartmentalization and modulating post-translational modifications, as well as the potential use of PDEs as disease biomarkers. Importantly, a more refined appreciation of the intramolecular mechanisms regulating PDE function and trafficking is emerging, making these pioneering drug discovery efforts tractable

Advances in targeting cyclic nucleotide phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants

Acetylsalicylic Acid

This book is the first and to date only compendium on the history, pharmacology, toxicology, and clinic of acetylsalicylic acid – not only the best known, but probably the most successful drug in medical history. Written by one of the world's leading experts in the field of aspirin research, it addresses the latest results of research by critically evaluating over 100 studies and summing up collected results from over 40 years of research

Receptor-Assisted Nanotherapeutics for Overcoming the Blood–Brain Barrier

Blood–brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor–based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB

Neurotransmitter-Related Molecular Modeling Studies

This book focuses of the neurotransmission phenomenon. By definition, neurotransmitters are chemicals that enable communication, i.e., the flow of nerve impulses between nerve cells or between nerve cells and muscles and glands. Recently, one can distinguish excitatory and inhibitory mediators, both of which are endo–exogenous compounds that control the function of the whole organism. From a chemical point of view, neurotransmitters belong to many different structural groups, such as amino acids (such as glycine), peptides (such as substance P, somatostatin), monoamines (such as noradrenaline or dopamine), purine derivatives (such as adenosine), gases (such as nitrogen, NO, carbon monoxide CO), and acetylcholine. From a medical point of view, disturbances in the concentration of neurotransmitters in the body result in the occurrence of mental disorders and diseases (such as depression, schizophrenia, Parkinson’s disease) and contribute to the occurrence of dementia (including Alzheimer’s disease), among other diseases. However, the problem is much wider. These disorders can lead to a number of cardiovascular diseases and can lead to the development of vascular diseases of the brain as well as in many other organs. Therefore, pharmacological intervention is a therapy that tries to interfere with regulatory processes year after year. Such treatments improve survival, reduce the frequency of readmission, and improve patients' quality of life