IN-VIVO PHARMACOLOGICAL PROFILE OF 9-HYDROXYRISPERIDONE, THE MAJOR METABOLITE OF THE NOVEL ANTIPSYCHOTIC RISPERIDONE

9-Hydroxyrisperidone (9OH-risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH-risperidone was compared with rispe ridone in a series of pharmacological tests in rats; ritanserin and ha loperidol were included as reference compounds in tests for 5HT(2) and D-2 antagonism, respectively. 9OH-risperidone closely resembled rispe ridone 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 blo ckade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescali ne head twitches (0.056/0.037 and 0.098/0.049); D-2 antagonism: inhibi tion and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inh ibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.5 9) and oxygen consumption (0.049/0.016 and 0.17/0.064), behavioral dis inhibition (0.069/0.031) and depression (4.6/4.7) in amphetaminized ra ts; histamine H-1, antagonism: protection from compound 48/80 lethalit y (0.018/0.014); alpha(1)-adrenoceptor antagonism: protection from nor epinephrine lethality (0.17/0.074); alpha(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 pa lpebral 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, BaCl2 and ouaba in, and did not block castor oil diarrhea. The acute oral LD(50) value s of the compounds were comparable. Both 9OH-risperidone and risperido ne differed markedly from haloperidol as indicated by: (1) predominant central 5HT(2) antagonism (comparable to that of ritanserin); (2) hig h doses of catalepsy; (3) gradual depression of motor activity; (4) pr onounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamine-induced oxygen consumption preceding inhibit ion of amphetamine agitation. As metabolic conversion of risperidone t o 9OH-risperidone does apparently not result in any marked change in a ctivity profile, its major consequence seems to be a prolongation of d uration of action. (C) 1994 Wiley-Liss, Inc.