S. Ahlenius et al., IN-VIVO EFFECTS OF REMOXIPRIDE AND AROMATIC RING METABOLITES IN THE RAT, The Journal of pharmacology and experimental therapeutics, 283(3), 1997, pp. 1356-1366
The in vivo effects of remoxipride, in relation to some of its identif
ied metabolites, were investigated in adult male Sprague-Dawley rats,
The methods used included: (1) estimation of the in vivo rate of brain
monoamine synthesis by measuring the accumulation of dihydroxyphenyla
lanine and 5-hydroxytryptophan after decarboxylase inhibition; (2) obs
ervations of spontaneous locomotor activity in a photocell-equipped op
en-field arena (approximate to 0.5 m(2)); (3) treadmill locomotion (ap
proximate to 4 m min(-1)); (4) inclined grid (60 degrees) catalepsy Ze
st; (5) d-amphetamine-induced (1.0 mg kg(-1)) hyperlocomotion;(6) quin
pirole-induced (0.4 mg kg(-1)) hypothermia. By use of one or-mo-re of
these tests, the findings with remoxipride were as follows: First, rem
oxipride had a late onset of action (up to 3 h). Second, potency and e
fficacy depended on exposure to hepatic metabolism Thus, intraperitone
al administration was more effective than the subcutaneous route, wher
eas virtually all biological effects were lost on intracerebroventricu
lar administration. The ED,, values (mu mol kg(-1), neostriatal dihydr
oxyphenylalanine accumulation) for remoxipride and a range of its phen
olic aromatic ring metabolites were: remoxipride (approximate to 20),
NCQ-344 (approximate to 0.01), FLA-797 (approximate to 0.1) FLA-908 (a
pproximate to 2.2), NCQ-436 (approximate to 25) and NCQ-469 (approxima
te to 30). Considering remoxipride as a nonclozapine atypical antipsyc
hotic drug, together with the fact that remoxipride behaves as a prodr
ug in the laboratory studies above, further characterization of the ph
armacodynamic profile of its metabolites remains a challenge.