Potential neuroleptic agents, N-[(2-pyrrolidinyl)methyl]-2,3-dihydrobenzofuran-7-carboxamide derivatives.
A series of 2,3-dihydrobenzofuran-7-carboxamides, presenting a stabilized intramolecular hydrogen bond, was synthesized and evaluated in pharmacological models for antipsychotic activity. Among them, N-[(1-butyl-2-pyrrolidinyl)methyl]-2-methyl-5-sulfamoyl-2, 3-dihydrobenzofuran-7-carboxamide (15) showed an atypical neuroleptic profile similar to that of sulpiride (1) and more lipophilic properties than 1. Compound 15 was 11 times more potent in antagonistic activity on apomorphine-induced hyperactivity in mice (ED50 = 30 mg/kg, p.o.) and stronger in potentiation of methamphetamine lethality in rats than 1, while it was as weak in inhibitory activity of apomorphine-induced stereotype in rats (ED50 greater than 500 mg/kg, p.o.) as 1. On the other hand, N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methyl-5-methylthio-2, 3-dihydrobenzofuran-7-carboxamide (30) showed a classical neuroleptic profile with a potency comparable to haloperidol in antagonistic activity on apomorphine-induced hyperactivity in mice (ED50 = 0.65 mg/kg, p.o.). The structure-activity relationships were also discussed.
Tahara
T
T
Central Research Laboratories, Yoshitomi Pharmaceutical Industries Ltd., Fukuoka, Japan.
Hayano
K
K
Murakami
S
S
Fukuda
T
T
Setoguchi
M
M
Ikeda
K
K
Marubayashi
N
N
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis*; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013239:Stereotyped Behavior / Q000187:drug effects
D014150:Antipsychotic Agents; D001572:Benzofurans; D011759:Pyrrolidines