FAUC 213, a highly selective dopamine D4 receptor full antagonist, exhibits atypical antipsychotic properties in behavioural and neurochemical models of schizophrenia.
BACKGROUND
2-[4-(4-Chlorophenyl)piperazin-1-ylmethyl]pyrazolo[1,5-a]pyridine (FAUC 213) is a highly selective antagonist at the dopamine D(4) receptor subtype. It was designed as a derivative of two partial antagonists and has been proven to be a complete antagonist in mitogenesis assay.


OBJECTIVE
In the present study, FAUC 213 was examined for antipsychotic properties in animal models of behavioural neurobiology and neurochemistry.


METHODS
Different concentrations of FAUC 213 were screened for effects on spontaneous, as well as amphetamine-induced, locomotor activity and apomorphine-induced prepulse disruption. The liability of causing extrapyramidal side effects was investigated in models of catalepsy and by high-performance liquid chromatography (HPLC) detection of dopamine turnover in several brain regions. The application schedule was validated, and the bioavailability of the compound determined, by means of a HPLC-pharmacokinetic study.


RESULTS
A significant effect in both the reduction of amphetamine-induced locomotor hyperactivity and the restoration of apomorphine-disrupted prepulse inhibition was found at 30 mg/kg. This dose proved not to be high enough to induce catalepsy or to increase dopamine turnover in the dorsal striatum, nucleus accumbens and medial prefrontal cortex. The selective D(4) antagonist FAUC 213, therefore, is not believed to mediate the above-mentioned effects via D(2) receptor antagonism, but a partial involvement of 5-HT(2)- and alpha(1)-receptors cannot be ruled out at present.


CONCLUSIONS
We have gathered evidence that FAUC 213 exhibits atypical antipsychotic characteristics.
Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zürich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland.
Frank
F
Boeckler
Holger
H
Russig
Weining
W
Zhang
Stefan
S
Löber
John
J
Schetz
Harald
H
Hübner
Boris
B
Ferger
Peter
P
Gmeiner
Joram
J
Feldon
D000661:Amphetamine; D000818:Animals; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050638:Receptors, Dopamine D4; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012565:Schizophrenic Psychology; D013997:Time Factors
C477900:2-(4-(4-chlorophenyl)piperazin-1-ylmethyl)pyrazolo(1,5-a)-pyridine; D065127:Dopamine D2 Receptor Antagonists; C493601:Drd4 protein, rat; D011720:Pyrazoles; D011725:Pyridines; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D000661:Amphetamine; D004298:Dopamine