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In vivo pharmacological profile of 9‐hydroxyrisperidone, the major metabolite of the novel antipsychotic risperidone
Author(s) -
Megens Anton A. H. P.,
Awouters Frans H. L.
Publication year - 1994
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.430330403
Subject(s) - ritanserin , pharmacology , risperidone , chemistry , antagonism , haloperidol , atypical antipsychotic , antipsychotic , endocrinology , medicine , serotonin , 5 ht receptor , dopamine , receptor , biochemistry , schizophrenia (object oriented programming) , psychiatry
9‐Hydroxyrisperidone (9OH‐risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH‐risperidone was compared with risperidone in a series of pharmacological tests in rats; ritanserin and haloperidol were included as reference compounds in tests for 5HT 2 and D 2 antagonism, respectively. 9OH‐risperidone closely resembled risperidone and showed similar effects at closely related doses (respective subcutaneous [sc] ED 50 s in mg/kg in parentheses): 5HT 2 antagonism: reversal of tryptamine cyanosis (0.00059/0.0011), inhibition and blockade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescaline head twitches (0.056/0.037 and 0.098/0.049); D 2 antagonism: inhibition and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inhibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.59) and oxygen consumption (0.049/0.016 and 0.17/0.64), behavioral disinhibition (0.069/0.31) and depression (4.6/4.7) in amphetaminized rats; histamine H 1 antagonism: protection from compound 48/80 lethality (0.018/0.014); α 1 ‐adrenoceptor antagonism: protection from norepinephrine lethality (0.17/0.074); α 2 ‐adrenoceptor antagonism: reversal of clonidine's antidiarrheal effect (0.29/0.67), reversal of xylazine loss of righting (16/2.4); and behavioral effects: slight and pronounced catalepsy (2.0/0.59 and 3.6/3.0), slight and pronounced palpebral ptosis (0.30/0.19 and 2.0/0.89), muscular hypotonia (4.7/3.6), hypothermia (4.1/2.0), inhibition of acetic acid writhing (1.2/0.34), and depression of motor activity (0.13/0.062 for vertical, 0.49/0.18 for horizontal, and 5.0/2.8 for total movements). Up to 10 mg/kg, both compounds were devoid of anti‐muscarinic and anti‐nicotinic activity, failed to affect the lethal effects of KCN, nitrogen, BaCl 2 and ouabain, and did not block castor oil diarrhea. The acute oral LD 50 values of the compounds were comparable. Both 9OH‐risperidone and risperidone differed markedly from haloperidol as indicated by: (1) predominant central 5HT 2 antagonism (comparable to that of ritanserin); (2) high doses of catalepsy; (3) gradual depression of motor activity; (4) pronounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamineinduced oxygen consumption preceding inhibition of amphetamine agitation. As metabolic conversion of risperidone to 9OH‐risperidone does apparently not result in any marked change in activity profile, its major consequence seems to be a prolongation of duration of action. © 1994 Wiley‐Liss, Inc.