The agonist activities of the putative antipsychotic agents, L‐745,870 and U‐101958 in HEK293 cells expressing the human dopamine D_4.4 receptor

Abstract

1 Dopamine D 4 receptor antagonists are being developed by several pharmaceutical companies as putative novel antipsychotics, possibly with low propensity to side-eects. Two such compounds, L-745,870 and U-101958 have been recently introduced. ]-spiperone binding was observed with spiperone (pK i 9.6+0.1, n=3), clozapine (pK i 7.4+0.1, n=4), L-745,870 (pK i 8.5+0.1, n=3) and U-101958 (pK i 8.9+0.1, n=3). By contrast, raclopride was very weak (pK i 55, n=3). 4 Dopamine inhibited forskolin-stimulated cyclic AMP accumulation in HEK293/D 4 cells in a concentration-dependent fashion (E max 71+2% inhibition of forskolin-stimulated levels, pEC 50 8.7+0.1, n=10). This eect was mimicked by the dopamine D 2 -like receptor agonists, quinpirole and 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT).

Certain 1,4-Disubstituted Aromatic Piperidines and Piperazines with Extreme Selectivity for the Dopamine D4 Receptor Interact with a Common Receptor Microdomain

“…For example, FAUC213, CP293,019, and Ro61-6270 are antagonists (Hartmann et al, 1996;Sanner et al, 1998;Lober et al, 2001); FAUC113, NGD 94-1, L750,667, and RBI257 are weak partial agonists (Gazi et al, 1998(Gazi et al, , 1999Lober et al, 2001); and PD168,077 and CP226,269 are agonists (Glase et al, 1997;Zorn et al, 1997), yet each of these ligands display mode-1 binding. Likewise, within mode-3 binding compounds there is no apparent correlation with their functional properties, because whereas PNU101,387G is an antagonist (Merchant et al, 1996), Ro10-4548 is an agonist (C. Riemer, personal communication).…”

“…Moreover, the clozapine-like structural analogs olanzapine and quetiapine both display a clozapine-like atypical antipsychotic clinical profile and have higher affinity for the D2 than the D4 subtype (ϳ3-4-and 14-fold, respectively; PDSP database, 2004). Although these later findings seemed to exclude D4 as a viable antipsychotic drug target, subsequent in vitro studies with L745,870 and other compounds considered initially to be highly D4-selective antagonists provided evidence for their weak partial agonist activity (Gazi et al, 1998(Gazi et al, , 1999.…”

D4 dopamine receptor-mediated phospholipid methylation and its implications for mental illnesses such as schizophrenia

“…9 While the clinical trial of a highly D4R-selective ligand (L-745870) did not reveal any benefit, 10 recent findings suggest this compound may in fact be an agonist, rather than an antagonist. 11 Structural features of the D4R suggest that it could play a unique role in neuropsychiatric disorders. Thus in humans and primates the D4R has a polymorphic 16 amino acid repeat in its third intracellular loop ( Figure 1) and humans can exhibit anywhere from two to ten repeats, 12,13 making the D4R one of the most hypervariable proteins in man.…”

JL13, a pyridobenzoxazepine compound with potential atypical antipsychotic activity, increases extracellular dopamine in the prefrontal cortex, but not in the striatum and the nucleus accumbens of rats

“…These findings should be judged with caution since there is no demonstration that these drugs block D 4 receptors in vivo. Moreover, L745,870 has partial agonist properties with a relatively high intrinsic activity (Gazi et al 1998).…”