RATIONALE: 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. OBJECTIVES: 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.
RATIONALE: 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. OBJECTIVES: 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.
Authors: L J Bristow; N Collinson; G P Cook; N Curtis; S B Freedman; J J Kulagowski; P D Leeson; S Patel; C I Ragan; M Ridgill; K L Saywell; M D Tricklebank Journal: J Pharmacol Exp Ther Date: 1997-12 Impact factor: 4.030
Authors: L Gazi; I Bobirnac; M Danzeisen; E Schüpbach; A T Bruinvels; S Geisse; B Sommer; D Hoyer; M Tricklebank; P Schoeffter Journal: Br J Pharmacol Date: 1998-07 Impact factor: 8.739
Authors: Enza Lacivita; Paola De Giorgio; Irene T Lee; Sean I Rodeheaver; Bryan A Weiss; Claudia Fracasso; Silvio Caccia; Francesco Berardi; Roberto Perrone; Ming-Rong Zhang; Jun Maeda; Makoto Higuchi; Tetsuya Suhara; John A Schetz; Marcello Leopoldo Journal: J Med Chem Date: 2010-10-28 Impact factor: 7.446
Authors: Neal R Swerdlow; Martin Weber; Ying Qu; Gregory A Light; David L Braff Journal: Psychopharmacology (Berl) Date: 2008-06-21 Impact factor: 4.530