RT Journal Article
SR Electronic
T1 <em>In Vivo</em> Effects of Remoxipride and Aromatic Ring Metabolites in the Rat
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1356
OP 1366
VO 283
IS 3
A1 Ahlenius, Sven
A1 Ericson, Evalena
A1 Hillegaart, Viveka
A1 Nilsson, Lars B.
A1 Salmi, Peter
A1 Wijkström, Agneta
YR 1997
UL http://jpet.aspetjournals.org/content/283/3/1356.abstract
AB The in vivo effects of remoxipride, in relation to some of its identified metabolites, were investigated in adult male Sprague-Dawley rats. The methods used included: (1) estimation of thein vivo rate of brain monoamine synthesis by measuring the accumulation of dihydroxyphenylalanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) observations of spontaneous locomotor activity in a photocell-equipped open-field arena (≈0.5 m2); (3) treadmill locomotion (≈4 m min−1); (4) inclined grid (60°) catalepsy test; (5)d-amphetamine-induced (1.0 mg kg−1) hyperlocomotion;(6) quinpirole-induced (0.4 mg kg−1) hypothermia. By use of one or more of these tests, the findings with remoxipride were as follows: First, remoxipride had a late onset of action (up to 3 h). Second, potency and efficacy depended on exposure to hepatic metabolism. Thus, intraperitoneal administration was more effective than the subcutaneous route, whereas virtually all biological effects were lost on intracerebroventricular administration. The ED50 values (μmol kg−1, neostriatal dihydroxyphenylalanine accumulation) for remoxipride and a range of its phenolic aromatic ring metabolites were: remoxipride (≈20), NCQ-344 (≈0.01), FLA-797 (≈0.1), FLA-908 (≈2.2), NCQ-436 (≈25) and NCQ-469 (≈30). Considering remoxipride as a nonclozapine atypical antipsychotic drug, together with the fact that remoxipride behaves as a prodrug in the laboratory studies above, further characterization of the pharmacodynamic profile of its metabolites remains a challenge. The American Society for Pharmacology and Experimental Therapeutics