Dopamine therapeutic targeting

Sokoloff P, Diaz J, Le Foil B, Guillin O, Leriche L, Bezard E et al (2006) The dopamine D3 receptor a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 5 25 3... 

A rich library of tracers exists for the dopamine Systran and perhaps also the serotonin system however, little or nothing currently exists for the assessment of many other neurotransmitter systems in the brain, some of whose receptors have been identified only recently. Pharmaceutical and biotechnology industries are major sources not only of new compounds that target these sites as candidate therapeutics but also of compounds that may serve as radiotracers to evaluate these sites and the effects of disease and treatment. The incentive and raw materials for continued development of functional imaging of the human bram will depend on the establishment of sustained collaborations between academic and government research centers and the pharmaceutical industry. 

To carry out design it is required, by definition, that an end point be identified. That is, what is the therapeutic goal Or, on the molecular level, what is the target for the drug The confusion over dopamine receptor subtypes will be commented on by others at this symposium but represents a serious obstacle to design of selective dopamine agonists. A focus on peripheral agonists simplifies matters, for at least in this... 

The first intracellular effect mediated by dopamine receptors that has been reported was the stimulation of the production of cyclic AMP (cAMP) in target cells. This effect was originally described in the superior cervical ganglia and the cow retina (Kebabian and Greengard, 1971 Brown and Makman, 1972) and soon afterward, in the CNS, in rat striatum (Kebabian et al., 1972). Antipsychotic drugs were found to block this response (Clement-Cormier et al., 1974 Miller et al., 1974) and this was the first direct evidence supporting the hypothesis proposed by A. Carlsson in the 1960s that the therapeutic actions of neuroleptics result from their ability to block dopamine receptors. 

Endogenous biogenic amines in the brain include catecholamines [NE (noradrenaline, NA), dopamine (DA), epinephrine (adrenaline)] 5-HT, histamine, and the so-called trace amines (P-phenylethylamine, tyramine, tryptamine, and octopamine). These amines have in common a arylalkylamine stmcture, and all have been implicated in the etiology of one or more psychiatric disorders and/or in therapeutic and/or adverse effects of drugs used to treat such disorders. In this review on depression, the focus in the case of biogenic amines will be on 5-HT, NE, and DA, although epinephrine and histamine and trace amines have also been implicated (see the section on Other Antidepressant Approaches and Targets ). 

Developmental malformations, impaired neuronal innervation, diminished parenchymal mass, metabolic compromise, and diminished dopamine tone in the frontal cortex typify schizophrenia but have little to do with dopamine receptors. The diminished transcription of genes for synaptogenesis, myeli-nation, metabolism, and development in the schizophrenic brain (8) may explain these impairments and are beginning to provide a novel set of targets for therapeutic intervention. 

All structures were selected from the Ensemble database. In addition to approved therapeutic agents these particularly include a set of lead compounds entered in advanced clinical/preclinical trials (a total of 16,540 compounds). Structures were extracted according to the assigned activity class, where the class indicates a common target-specific group such as GPCRs, kinases and proteases, nuclear receptors, and ion channels as well as more than 150 subclasses (for example, serotonin, tachykinin and dopamine receptors, tyrosine, Abl, Aurora and serine/threonine kinases, cysteine and serine proteases, etc.). Prior to the statistical experiments, the molecular structures should be filtered and normalized in order to fulfill certain criteria (see Subheading 3.5 and 4). 

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