Dopamine D4 Receptors: A New Opportunity for Research on Schizophrenia

Abstract

Classically, the D2 receptors formed the core of the dopamine hypothesis for schizophrenia. Recently, the dopamine D4 receptors have received particular attention in this context. This is due to the atypical antipsychotic, clozapine, which is effective in treating refractory schizophrenics without the side-effect profile of typical neuroleptics, and displays a ten-fold higher affinity for D4 compared to D2 or D3 receptors. Following various . reports presenting the interest of D4 receptors in treating schizophrenia, multiple chemical developments were made. During the last five years, various structures were described with a high selectivity for D4 receptor subtype. Currently, although the first clinical report was very disappointing, the observation which support the idea that D4 might serve as a target for clozapine have significantly modified and extended the understanding of mechanism underlying atypical antipsychotic treatment of schizophrenia.

N-[2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide: A Potent and Selective Dopamine D4 Ligand

“…Elemental analyses (C, H, N) were performed on a Carlo Erba model 1106 analyzer; the analytical results were within (0.4% of the theoretical values for the formula given. 1 H NMR spectra were recorded either on a Varian EM-390 where indicated 90 MHz (TMS as internal standard) or on a Bruker AM 300 WB instrument, with CDCl3 as solvent; all values are reported in ppm (δ). Recording of mass spectra was done on a HP 5995C gas chromatograph/mass spectrometer, electron impact 70 eV, equipped with HP59970A workstation; only significant m/z peaks, with their % relative intensity in parentheses, are herein reported.…”

“…From a survey of the recent literature, it is clear that the discovery of ligands for dopamine D 4 receptor is a priority for many research laboratories . Interest in this area is due to the speculation about the possible involvement in schizophrenia of D 4 receptors. − In the early 1990s molecular biology techniques showed that the D 2 -like receptors are subdivided into D 2 , D 3 , and D 4 subtypes. − This latter receptor subtype is located in cortical and other areas of the brain believed to control emotional and cognitive functions. , Most clinically effective classical antipsychotic drugs bind at dopamine D 2 -like receptors, including the D 4 subtype, at therapeutically relevant concentration .…”

“…From a survey of the recent literature, it is clear that the discovery of ligands for dopamine D 4 receptor is a priority for many research laboratories. 1 Interest in this area is due to the speculation about the possible involvement in schizophrenia of D 4 receptors. [2][3][4][5] In the early 1990s molecular biology techniques showed that the D 2 -like receptors are subdivided into D 2 , D 3 , and D 4 subtypes.…”

1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1,3-dihydroimidazol-2-one: A Selective High-Affinity Antagonist for the Human Dopamine D4Receptor with Excellent Selectivity over Ion Channels

“…The solvent was removed by rotary evaporation, and the residue was triturated with Et 2O and then collected by filtration to give 1-benzyl-4-(tert-butyloxycarbonylamino)piperidine as a white solid (60. 29 To a suspension of 1-benzyl-4-(tert-butyloxycarbonylamino)piperidine (60.29 g, 0.20 mol) in methanol (700 mL) was added (under nitrogen) 10% palladium on carbon catalyst (3.0 g), and the mixture was shaken under 50 psi of hydrogen for 18 h. The solution was filtered and the solvent was removed by rotary evaporation to give 4-(tert-butyloxycarbonylamino)piperidine as a white solid (40 g, 97%): mp 153-155 °C; 1 To a suspension of 4-(tert-butyloxycarbonylamino)piperidine (3.5 g, 0.0175 mol) in dimethylformamide (10 mL) were added ethyldiisopropylamine (6.1 mL, 0.035 mol) and 2-bromoethylbenzene (2.64 mL, 0.0193 mol), and the solution was stirred at room temperature for 42 h under nitrogen. The reaction mixture was poured into water (500 mL) and extracted with CH 2Cl2 (3 × 250 mL).…”

“…There are five cloned subtypes of the human dopamine receptor which have been divided into two pharmacological classes: D 1 -like (D 1 and D 5 ) , and D 2 -like (D 2 , D 3 , and D 4 ). − Classical neuroleptic drugs such as haloperidol are believed to work through nonselective antagonism of D 2 -like dopamine receptors; however, severe movement disorders are also manifested (probably due to blockade of D 2 receptors in the striatum) along with hyperprolactinemia . Since the revelation 6 that the atypical neuroleptic clozapine ( 1 ; Table ), which treats both the positive and negative symptoms of schizophrenia without producing extrapyramidal side effects, has higher affinity for the human dopamine D 4 receptor than the D 2 receptor, there has been a huge surge of interest in the D 4 area as a possible new approach toward the treatment of schizophrenia. − …”