Abstract
The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.
Keywords:
Antipsychotic; Benzoxazole; Piperazine; Piperidine.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
-
Animals
-
Antipsychotic Agents / chemical synthesis*
-
Antipsychotic Agents / pharmacology
-
Antipsychotic Agents / toxicity
-
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
-
Humans
-
Mice
-
Oxazoles / chemical synthesis*
-
Oxazoles / pharmacology
-
Oxazoles / toxicity
-
Patch-Clamp Techniques
-
Piperazines / chemical synthesis*
-
Piperazines / pharmacology
-
Piperazines / toxicity
-
Piperidines / chemical synthesis*
-
Piperidines / pharmacology
-
Piperidines / toxicity
-
Potassium Channel Blockers / chemical synthesis
-
Potassium Channel Blockers / pharmacology
-
Potassium Channel Blockers / toxicity
-
Rats
-
Receptors, Dopamine D2 / agonists
-
Schizophrenia / drug therapy*
-
Serotonin 5-HT1 Receptor Agonists / chemical synthesis
-
Serotonin 5-HT1 Receptor Agonists / pharmacology
-
Serotonin 5-HT1 Receptor Agonists / toxicity
-
Serotonin 5-HT2 Receptor Agonists / chemical synthesis
-
Serotonin 5-HT2 Receptor Agonists / pharmacology
-
Serotonin 5-HT2 Receptor Agonists / toxicity
-
Structure-Activity Relationship
-
Swine
Substances
-
3-(1-(3-(4-(benzo(d)oxazol-2-ylmethyl)phenoxy)propyl)piperidin-4-yl)-6-fluorobenzo(d)isoxazole
-
Antipsychotic Agents
-
Ether-A-Go-Go Potassium Channels
-
KCNH1 protein, human
-
Oxazoles
-
Piperazines
-
Piperidines
-
Potassium Channel Blockers
-
Receptors, Dopamine D2
-
Serotonin 5-HT1 Receptor Agonists
-
Serotonin 5-HT2 Receptor Agonists