3-[[(Aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles as D2/5-HT2 antagonists with potential atypical antipsychotic activity: antipsychotic profile of iloperidone (HP 873).
A series of 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazoles was synthesized and evaluated as potential antipsychotic D2/5-HT2 antagonists. Most of these compounds showed potent antipsychotic-like activity in an apomorphine-induced climbing mouse paradigm, with many also showing preferential mesolimbic activity, as indicated by their weaker effects in an apomorphine-induced stereotypy model. In receptor binding assays, many displayed a moderate affinity for the D2 receptor coupled with a significantly greater affinity for the 5-HT2 receptor: a property that has been suggested as necessary for atypicality. From this series, compound 45, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- piperidinyl]propoxy]-3-methoxyphenyl]ethanone (iloperidone, HP 873), was further evaluated in a battery of in vivo and in vitro assays. This compound showed a 300-fold greater potency in inhibition of climbing than in inhibition of stereotypy or induction of catalepsy, and when evaluated chronically in an electrophysiological model, 45 caused a depolarization blockade of dopamine neurons in the A10 area of the rat brain but not in the A9 area. Additionally, it showed positive activity in a social interaction paradigm, suggesting potential efficacy against asociality, a component of the negative symptoms of schizophrenia. In chronic ex vivo studies, 45, similar to clozapine, caused a down regulation of 5-HT2 receptors but had no effect on the number of D2 receptors. Compound 45 is currently undergoing clinical evaluation.
Strupczewski
J T
JT
Chemical Research Department, Hoechst-Roussel Pharmaceuticals Inc, Somerville, New Jersey 08876, USA.
Bordeau
K J
KJ
Chiang
Y
Y
Glamkowski
E J
EJ
Conway
P G
PG
Corbett
R
R
Hartman
H B
HB
Szewczak
M R
MR
Wilmot
C A
CA
Helsley
G C
GC
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001522:Behavior, Animal / Q000187:drug effects; D018492:Dopamine Antagonists / Q000138:chemical synthesis; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D007555:Isoxazoles; D010880:Piperidines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D001058:Apomorphine; C081732:iloperidone