Abstract：
:1-(3'-Chlorophenyl)-3-[2-(3,3-dimethyl-1-azetidinyl)ethyl] imidazolidin-2-one, zetidoline, a new neuroleptic agent, when incubated with rat liver microsomes was rapidly metabolized to six free (mets B, D, I, L, M and N) and two conjugated metabolites (mets E and F). Sites of the metabolic attack (oxidation) were primarily the aromatic moiety, then the imidazolidinone and the azetidine rings. The metabolites were purified and structures assigned by means of EI-MS, 1H-NMR and chemical synthesis (mets B, D, L and M). The main metabolites, zetidoline, some chemical analogues and a few known dopamine antagonists were tested as in vitro inhibitors of 3H-zetidoline and 3H-spiperone binding to rat striatal membranes, and as in vivo inducers of prolactin release in female rats (inhibition of the estrus cycle). Two zetidoline metabolites, namely 4'-hydroxy zetidoline (met. B) and 5-hydroxy zetidoline (met. L), were found to have both in vitro and in vivo activities comparable to those of the parent drug. Identification of these active hydroxylated metabolites appears important both in the search of new leads of neuroleptics and for designing pro-drugs derivatives with improved pharmacokinetic profiles.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Assandri A,Galliani G,Zerilli L,Tuan G,Tarzia G,Barone Ddoi
10.1016/0006-2952(86)90110-3subject
Has Abstractpub_date
1986-05-01 00:00:00pages
1459-67issue
9eissn
0006-2952issn
1873-2968pii
0006-2952(86)90110-3journal_volume
35pub_type
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