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.