Emerging Drugs and Targets for Parkinson's Disease

It was first

described in 1817 by the British physi- cian James Parkinson in his Essay on the Shaking Palsy. The patients suffer from motoric symptoms (bradykinesia or aki- nesia, tremor and rigor, postural instabili- ty), vegetative manifestations (e.g. , sweating, hypersalivation, obstipation, sleep disturbance, hypotonia), and psy- chological and cognitive symptoms (de- pression, dementia). Different forms of PD exist, which show variable severity of symptoms. Progressive degeneration of dopaminergic neurons in the basal gan- glia is observed which leads to an imbal-

　

ance in neurotransmitter levels and a dis- turbance of dopaminergic signaling. The underlying cause is in most cases unclear and therefore termed "idiopathic". A milestone in the development of PD was the discovery of levodopa (l-DOPA)— a precursor of dopamine in the 1960s— which is still the gold-standard in PD therapy, applied in combination with a peripheral DOPA decarboxylase inhibi- tor to increase its bioavailability in the brain. Further, currently used drugs for PD include dopamine agonists, inhibitors of l-DOPA and dopamine degradation (monoamine oxidase or MAO inhibitors and catecholamine-O-methyltransferase or COMT inhibitors), and glutamate re- ceptor antagonists (e.g. , memantine). However, PD can only be symptomatical- ly treated, and its chronic progression cannot be stopped by currently available therapeutics. In addition, levodopa treat- ment causes severe side-effects in many patients after long-time treatment, such as dyskinesia (involuntary movements), and, after some years, it tends to become ineffective. Thus, there is a strong medical need for novel thera- peutics that are neuroprotective, stop- ping (or even reversing) the neurodege- nerative process. New diagnostic meth- ods are required to allow an early diag- nosis as a prerequisite for a neuroprotec- tive therapy. Furthermore, the broad range of symptoms is currently only partly addressed by available drugs. Es- pecially in patients with advanced PD, additional non-motoric symptoms, such as depression and dementia, gain impor- tance.

This book, edited by medicinal chem- ists with a strong background in drug development for neurodegenerative dis- eases, in particular Alzheimer’s disease (AD), provides a broad overview of the topic. The 17 chapters are subdivided into five different sections : introduction (Chapter 1 and 2), l-DOPA and dopamin- ergic agents (Chapters 3–7), the a-synu- clein hypothesis (Chapter 8), neuropro- tective therapies (Chapters 9–15), and neuroregenerative strategies (Chapter 16 and 17). Most of the chapters start with an introduction and end with conclu- sions and perspectives.

The introductory chapters describing the current state of knowledge on

pathogenesis, pathophysiology, symp- toms, unmet medical needs, and new therapeutic targets are excellent. They provide an (almost) comprehensive basis for a medicinal chemist or pharmacolo- gist working in the field.

In subsequent chapters, besides the targets for drugs that are already on the market, the following new approaches are covered in some detail : protein phosphatases, a-synuclein, glutamate re- ceptor subtypes, LRRK2 kinase, phospho- diesterases, serotonin 5-HT1A receptor,

tryptophan metabolism, P2X7 purine

(ATP) receptor, carotid body transplanta- tion, and stem-cell therapy. This appears to present a subjective selection of po- tentially important targets for future AD therapeutics, which are in a more or less advanced state of development. Some of the covered targets are merely on the level of basic research, while drugs for other reviewed targets are already in

　

clinical evaluation. Consistently and opti- mistically, the editors state in the pref- ace : "This book collects some of the most outstanding examples of new drugs under pharmaceutical development or new tar- gets in the validation process that will reach the Parkinson’s drug market over the next few years as disease-modifying drugs."

The selection of targets is limited, and some important topics appear to be missing. For example, adenosine A2A re- ceptor antagonists are only incidentally mentioned and missing in the subject index, although the first A2A antagonist, istradefylline (Nouriast•) was approved in May 2013 in Japan for adjunctive treatment of PD. Even though the out-

come of phase III clinical trials of another A2A antagonist, preladenant, did not result in further pursuing its registration as a drug, several other A2A antagonists are in preclinical and clinical develop-

　

ment. This new class of PD therapeutics may be truly neuroprotective and dis- ease modifying, and might also show positive effects on concomitant symp- toms, such as depression and restless legs syndrome as indicated by animal studies.

The book is of good-quality paper and relatively well edited. The focus is more on targets than on compounds, and there are a number of colored schemes illustrating the discussed signaling path- ways. Altogether, I can recommend this volume of the excellent RSC Drug Dis- covery Series to medicinal chemists, (chemical) biologists and pharmacolo- gists interested in drug development for Parkinson’s disease.

Parkinson’s dis- ease (PD) is one of the most prevalent neu- rological and neurodegenera- tive diseases with increasing numbers of pa- tients in indus- trialized coun- tries due to an ageing popula- tion.

* Chemmedchem *

"The introductory chapters describingn the current state of knowledge on pathogenesis, pathophysiology, symptoms, unmet medical needs, and new therapeutic targets are excellent." "The following new approaches are covered in some detail: protein phosphatases, a-synuclein, glutamate receptor subtypes, LRRK2 kinase, phosphodiesterases, serotonin 5-HT1A receptor, tryptophan metabolism, P2X7 purine (ATP) receptor, carotid body transplantation, and stem-cell therapy. This appears to present a subjective selection of potentially important targets for future AD therapeutics." "Altogether, I can recommend this volume of the excellent RSC Drug Discovery Series to medicinal chemists, (chemical) biologists and pharmacologists interested in drug development for Parkinson’s disease."

* Chemmedch