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SCH 39166, a novel dopamine D1 receptor antagonist: In vitro investigation of its glucuronidation and potential species differences
Author(s) -
Tedford Clark E.,
Ruperto Vilma B.,
Coffin Vicki L.,
Cohen Mary,
Libonati Michele,
Barnett Allen
Publication year - 1992
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430260403
Subject(s) - sch 23390 , glucuronidation , squirrel monkey , pharmacology , antagonist , microsome , in vivo , dopamine , dopamine antagonist , chemistry , in vitro , biology , endocrinology , medicine , receptor , biochemistry , neuroscience , microbiology and biotechnology
SCH 39166 is a novel benzonaphthazepine that is a selective dopamine D1 receptor antagonist. It is currently undergoing clinical trials in humans for possible use as an antipsychotic medication. To date, no studies have been presented describing the metabolism of SCH 39166. Therefore, the present studies investigated the possible in vitro glucuronidation of SCH 39166 from both rodent and squirrel monkey liver microsomes. Comparisons were made with the classic D1 antagonist, SCH 23390, a benzazepine which undergoes extensive glucuron dation in the rat. Additionally, dose response and duration of action of SCH 39166 on the conditioned avoidance paradigm (CAR) in both rats and squirrel monkeys were compared to the dose response and duration of action of SCH 23390 in these species. Results demonstrated that 3 H‐SCH 39166 was glucuronidated by both rat and monkey liver microsomes. In studies with rat liver microsomes, the rate of glucuronidation of SCH 39166 and the affinity for the glucuronosyltransferase enzyme were equivalent to those of SCH 23390. In vivo behavioral studies also indicated no differences in either the dose‐response curves or the time course of behavioral effects for either D1 antagonist after oral administration in the rat. In contrast, the rate of glucuronidation in squirrel monkey liver microsomes of SCH 23390 was 3–4 times faster than that of SCH 39166. Moreover, these findings consistent with in vivo behavioral studies in squirrel monkeys, in which the duration of action of SCH 23390 was much shorter than SCH 39166. © 1992 wiley‐Liss, Inc.