A comparison of the selectivities of SCH 23390 with BW737C89 for D1, D2 and 5-HT2 binding sites both in vitro and in vivo

The in vitro affinities (K_Is) for SCH 23390 in D₁, D₂ and 5-HT₂ binding assays were 0.4, 631 and 20 nM as compared with 0.3, 79 and 79 nM for BW737C89. The K_B values, derived from their abilities to right-shift dopamine-mediated dose-dependent increases in striatal adenylyl cyclase activity, were 0.8 and 0.5 nM for SCH 23390 and BW737C89, respectively. Thus, BW737C89 was a highly potent dopamine D₁ receptor antagonist and, although it was less D₁/D₂-selective than SCH 23390, it was more D₁/5-HT₂-selective. Both SCH 23390 and BW737C89 (0.1–100 μmol/kg s.c.) exhibited a selective dose-dependent protection of D₁, but not D₂, binding, from inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 8 mg/kg s.c.) as measure by [³H]SCH 23390 (D₁) and [³H]spiperone (D₂) binding. The ED₅₀ values for this selective protection of D₁ binding were similar and were between 1 and 3 μmol/kg s.c. BW737C89 showed no protective effect at all on the inactivation of [³H]ketanserin (5-HT₂) binding by EEDQ whereas SCH 23390 started to show protection at doses of 10 μmol/kg. s.c. and above. A direct comparison of the time course of the effects of pretreatment of a dose of 30 μmol/kg s.c. of both compounds to protect 5-HT₂ binding was carried out. This study confirmed the complete lack of protective effect of BW737C89 from 1 to 4 h of pretreatment whereas SCH 23390 exhibited 62, 29 and 28% protection at 1,2 and 4 h pretreatment respectively. Thus, these data clearly show that BW737C89 is a potent and selective D₁ antagonist which is more selective for D₁ receptors in vivo than is SCH 23390.