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 (KIs) 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 KB 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 mumol/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 measured 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 mumol/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 mumol/kg s.c. and above. A direct comparison of the time course of the effects of pretreatment of a dose of 30 mumol/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemical Sciences, Wellcome Research Laboratories, Beckenham, Kent, U.K.
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Riddall
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044005:Tetrahydroisoquinolines
D000317:Adrenergic alpha-Antagonists; D001552:Benzazepines; D018492:Dopamine Antagonists; D007546:Isoquinolines; D011804:Quinolines; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044005:Tetrahydroisoquinolines; C075318:BW 737C89; C000470:EEDQ