7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics. 2. Pharmacological profile of 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-piperidin-1-yl]propoxy]-3-(hydroxymeth yl)chromen -4-one (abaperidone, FI-8602).
A series of novel 7-[3-(1-piperidinyl)propoxy]chromenones was synthesized and tested as potential antipsychotics in several in vitro and in vivo assays. The compounds possessed good affinity for D2 receptors, together with a greater affinity for 5-HT2 receptors, a profile which has been proposed as a model for atypical antipsychotics. Several agents also displayed a high potency in the climbing mice assay on oral administration, suggesting a potent antipsychotic effect as compared to reference standards. Compound 23 was selected for further pharmacological evaluation. Induction of catalepsy and inhibition of stereotypies weaker than standards, along with a lower increase in serum prolactin levels, were indicative of a potential atypical profile for this compound. From these results, 7-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperidin-1-yl]propoxy]-3-(hydroxymethyl )chromen- 4-one (23, abaperidone) has been proposed for clinical evaluation in humans as a potential atypical antipsychotic.
Bolós
J
J
Departments of Medicinal Chemistry, Pharmacology, and Biochemistry, Centro de Investigación Grupo Ferrer, Juan de Sada, 32, 08028-Barcelona, Spain.
Anglada
L
L
Gubert
S
S
Planas
J M
JM
Agut
J
J
Príncep
M
M
De la Fuente
N
N
Sacristán
A
A
Ortiz
J A
JA
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D011388:Prolactin / Q000097:blood; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D002867:Chromones; D007555:Isoxazoles; D017981:Receptors, Neurotransmitter; C116717:abaperidone; D011388:Prolactin