title: New small molecules for the treatment of Parkinson's disease.
abstract: BACKGROUND
  Parkinson's disease (PD) is characterized by a slowly ongoing neuronal death, which affects neurotransmitter metabolism and causes a wide variety of motor and non-motor features. Until now, therapy approaches have predominantly focused on motor behavior associated with dopamine substitution.
  
  
  METHODS
  This review aims to discuss putative reasons for recent failures of investigated treatment approaches, and to introduce currently tested and future compounds.
  
  
  RESULTS
  We will describe how development programs of novel molecules now additionally consider non-motor features of PD as promising targets in order to obtain regulatory approval. Regulatory authorities increasingly exert influence on trial designs, demanding therapeutic effects that are not always clinically feasible given the variety of manifestations of the disease entity known as PD.
  
  
  CONCLUSIONS
  In the past, research pitfalls have resulted in the failure of promising new compounds. Among the many reasons for this are massive placebo responses; the participation of too many investigators, with consequent wide variations of efficacy assessments; and a misconception of preclinical drug development, with models of PD that do not mimic its clinical nature. A few compounds are now being tested that have modes of action indirectly modulating the dopamine system; however, critical analysis of the preclinical and clinical research concept and drug approval is warranted to prevent further frustration in this field.
authors.affiliation: St. Joseph Hospital Berlin-Weissensee, Department of Neurology, Gartenstrasse 1, 13088 Berlin, Germany. th.mueller@alexius.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
mesh_terms: D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D018450:Disease Progression; D004298:Dopamine / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D020820:Dyskinesias / Q000188:drug therapy; D015316:Genetic Therapy; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D054852:Small Molecule Libraries; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D018696:Neuroprotective Agents; D054852:Small Molecule Libraries; D004298:Dopamine