A novel series of arylpiperazines with high affinity and selectivity for the dopamine D3 receptor

Heterogeneity of behavioural profile between three new putative selective D 3 dopamine receptor antagonists using an ethologically based approach

“…a P < 0.05, b P < 0.01, c P < 0.001 versus vehicle (V ); *P < 0.05, **P < 0.01 versus U99194A Both the selective D 3 antagonist GR 103691, having a > 100-fold D 3 /D 2 a¦nity ratio (Murray et al 1995), and the preferential D 3 antagonist nafadotride, having a 10-fold D 3 /D 2 a¦nity ratio (Sautel et al 1995b), were without e¤ect on any aspect of spontaneous behaviour, as evaluated using an ethologically based technique sensitive to all behaviours in the rodent repertoire; thus, we could identify no ethogram for either of these drugs. There are no previous reports examining the e¤ects of GR 103691 on spontaneous behaviour, and the present dose range was based on its ED 50 for blockade of locomotor activity induced by intracerebral injection of the GABA A agonist muscimol into the ventral tegmental area (Murray et al 1995). Nafadotride has been reported to induce a modest but signiÞcant increase in photobeam interuptions over a narrow dose range; we were unable to identify any comparable e¤ect over a similar dose range, and it was not possible to address issues of potential di¤erences in rat strain, age and gender in the absence of such information in that report (Sautel et al 1995b).…”

“…Recently, U99194A was identiÞed and shown to have 25-fold selectivity for D 3 over D 2 sites and to induce behavioural stimulation in the absence of any concomitent change in DA release, consistent with blockade of postsynaptic D 3 receptors (Waters et al 1993). Subsequently, nafadotride has been identiÞed as having a 10-fold preference for D 3 over D 2 receptors and to induce behavioural stimulation (Sautel et al 1995b) while GR 103691, identiÞed as having > 100-fold selectivity for D 3 over D 2 receptors (Murray et al 1995), has yet to be studied in this manner. Importantly, examination of the e¤ects of selective D 3 antagonists on spontaneous behaviour in the rat has been conducted separately and using automated procedures, i.e.…”

Current drug treatments targeting dopamine D3 receptor

“…ligands has led to development of bitopic D3R compounds (Murray et al, 1995;Murray et al, 1996). A bitopic ligand is characterized by two pharmacophores, the primary and the secondary one, joint through a linker.…”

Synthesis and radiolabelling of [123I]‐4‐iodo‐N‐(4‐(4‐(2‐methoxyphenyl)‐piperazin‐1‐yl)butyl)‐benzamide, a potential dopamine D3 antagonist for SPECT studies

“…Apart from dopamine receptors there is some interaction with the 5-HT 1A receptor (pK i =7.9) and the a 1 receptor (pK i =7.9). 8 From these data we can assume that the iodinated derivative will also show selectivity for the D 3 receptor moreover since antagonists with larger groups in the same position also show D 3 selectivity (e.g. aminobenzyl: pK i D 3 = 9.7, pK i D 2 =7.7).…”

“…First of all the tracer needs to have high affinity for the dopamine D 3 receptor due to the low density of these receptors, furthermore the selectivity over the other dopamine receptor subtypes and other receptor types in general needs to be good and finally the lipophilicity should not be too high in order to avoid non-specific binding. Selection of [ 123 I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-1-piperazinyl) butyl)-benzamide as a potential tracer for the D 3 receptor was based upon data collected by Murray et al 8 These data indicate that the corresponding bromated derivative has high affinity for the D 3 receptor (pK i =9.3) and shows a 100 fold selectivity over the D 2 (pK i =7.4) and D 4 (pK i =7.3) receptors. Apart from dopamine receptors there is some interaction with the 5-HT 1A receptor (pK i =7.9) and the a 1 receptor (pK i =7.9).…”