Novel benzothiazolin-2-one and benzoxazin-3-one arylpiperazine derivatives with mixed 5HT1A/D2 affinity as potential atypical antipsychotics.
Since it was known that 5HT properties (5HT1A agonism or 5HT2A antagonism) combined with D2 antagonism may lead to atypical antipsychotic drugs, a series of 19 benzothiazolin-2-one and benzoxazin-3-one derivatives possessing the arylpiperazine moiety was prepared, and their binding profiles were investigated. All tested compounds displayed very high affinities for the 5HT1A and D2 receptors. Therefore, further pharmacological studies were carried out on selected compounds (24, 27, 30, 46, and 47). This evaluation in rats clearly revealed potent antipsychotic properties along with a decrease of extrapyramidal side effects. These derivatives are currently under preclinical development.
Taverne
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Institut de Chimie Pharmaceutique, 3 rue du Professeur Laguesse, BP 83, F-59006 Lille Cedex, France.
Diouf
O
O
Depreux
P
P
Poupaert
J H
JH
Lesieur
D
D
Guardiola-Lemaître
B
B
Renard
P
P
Rettori
M C
MC
Caignard
D H
DH
Pfeiffer
B
B
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006948:Hyperkinesis / Q000188:drug therapy; D051379:Mice; D010078:Oxazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D010078:Oxazines; D010879:Piperazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D013844:Thiazoles