Synthesis and pharmacological evaluation of some 3-[(4-aryl and benzylpiperazinyl) alkoxy]-2-methyl-4-(3H)-quinazolinones as potential neuroleptic agents

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A series of 3-[2 and 3-(4-(aryl- and benzylpiperazinyl)alkoxy]-2-methyl-4(3H)-quinazolinones (7a-t) and corresponding dihydrochlorides (7a, d-f, h-l, n-t. 2HCl) were synthesized. The dihydrochloride salts (7a-t. 2HCl) were tested for their neuroleptic activity in an apomorphine-induced climbing paradigm. Inhibition of apomorphine-induced stereotypy and induction of catalepsy were also assessed for the active compounds and compared with haloperidol (typical neuroleptic) and clozapine (atypical neuroleptic) as positive controls. Compounds, (7m, q, r, s. 2HCl) showed neuroleptic activity in apomorphine-induced climbing test in doses less than 60 mg/kg orally. The best pharmacological profile was obtained with 3-[3-[4-(3-Trifluorotolyl)piperazinyl]propoxy] -2-methyl-4-(3H)quinazolinone dihydrochloride (7s. 2HCl), which showed a greater potency in inhibition of apomorphine-induced climbing (ED 50 = 30.9 mg/Kg, po) than in inhibition of apomorphine-induced stereotypy (ED 50 = 73.3 mg/Kg, po) or induction of catalepsy (ED 50 > 200 mg/Kg, po), indicative of lower side effects than haloperidol. Also, the effect of structural modification upon activity was explored.

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