Bitropic D3 dopamine receptor selective compounds as potential antipsychotics

Robert T. Luedtke, Claudia Rangel-Barajas, Mahinder Malik, David E. Reichert, R. H. Mach

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be modified to develop bivalent ligands capable of interacting with receptor dimers or oligomers are also provided. Preclinical studies using bitropic D3 dopamine receptor selective ligands are also discussed as strategy to pharmacologically dissect the role of the D2 and D3 dopamine receptor subtypes in animal models of neuropsychiatric, neurological and substance abuse disorders. This research has the potential to a) advance the understanding of the role of the D2 and D3 dopamine receptor subtypes in neuropsychiatric disorders and b) lead to new treatment strategies for neuropsychiatric disorders.

Original languageEnglish
Pages (from-to)3700-3724
Number of pages25
JournalCurrent Pharmaceutical Design
Volume21
Issue number26
DOIs
StatePublished - 1 Sep 2015

Fingerprint

Dopamine D3 Receptors
Antipsychotic Agents
Dopamine D2 Receptors
Dopamine D4 Receptors
Ligands
Gynecomastia
Delusions
Hallucinations
Dopamine Receptors
National Institutes of Health (U.S.)
Dyslipidemias
Hyperglycemia
Prolactin
Cognition
Weight Gain
Substance-Related Disorders
Schizophrenia
Diabetes Mellitus
Emotions
Therapeutics

Keywords

  • Biased agonism
  • Bitropic ligands
  • Bivalent ligands
  • D2-like dopamine receptors
  • D3 dopamine receptor subtype
  • D3 receptor preclinical studies
  • Dopamine receptors
  • Functional selectivity
  • G-protein coupled receptors
  • Receptor subtype selectivity

Cite this

Luedtke, Robert T. ; Rangel-Barajas, Claudia ; Malik, Mahinder ; Reichert, David E. ; Mach, R. H. / Bitropic D3 dopamine receptor selective compounds as potential antipsychotics. In: Current Pharmaceutical Design. 2015 ; Vol. 21, No. 26. pp. 3700-3724.
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Bitropic D3 dopamine receptor selective compounds as potential antipsychotics. / Luedtke, Robert T.; Rangel-Barajas, Claudia; Malik, Mahinder; Reichert, David E.; Mach, R. H.

In: Current Pharmaceutical Design, Vol. 21, No. 26, 01.09.2015, p. 3700-3724.

Research output: Contribution to journalArticle

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