Metabolites of haloperidol display preferential activity at σ receptors compared to dopamine D-2 receptors

Development and validation of a HPLC-UV method for 4-(4-chlorophenyl)-4-hydroxypiperidine (CPHP), a toxic metabolite of haloperidol, in humans: providing in vivo evidence of CYP3A4-mediated CPHP formation

“…[1,9,10] Consistently, our results showed, itraconazole, a CYP3A4 inhibitor, [19] reduced the urinary recovery of CPHP, suggesting the involvement of CYP3A4 in the formation of CPHP from haloperidol in human.…”

“…Even though the pharmacological role of CPHP is not understood fully, CPHP showed an affinity to sigma receptor, [2,10] and a potent inhibition on dopamine uptake in rat brain slices. [5] Haloperidol is used to treat psychiatric diseases for longperiods of time, but there has been no available data to show that CPHP is an in vivo metabolite of haloperidol in human.…”

“…[9] CPHP has a moderate affinity to the sigma receptor, suggesting that it may mediate neurological side effects and a potent inhibition of dopamine uptake in the brain. [10,11] Structurally, CPHP resembles 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which induces severe neurotoxicity, including Parkinsonlike disease and dyskinesia. [12,13] Therefore, these symptoms TCP Transl Clin Pharmacol CYP3A4-mediated CPHP formation in humans from patients treated with haloperidol might result from CPHP accumulation.…”

Differentiation of σ ligand‐activated receptor subtypes that modulate NMDA‐evoked [3H]‐noradrenaline release in rat hippocampal slices

“…Figure 1 shows that haloperidol (300 nM) was very effective in preventing the potentiating effect of (+ )-pentazocine (100-300 nM; Figure ( Figures 5 and 6) and shifted the response curve of BD-737 to the right ( Figure 5). Reduced haloperidol, BD-1008 and NE-100, which all exhibit selectivity and high affinity for a sites Bowen et al, 1990;Okuyama et al, 1993;Klein et al, 1994) concentration-dependently (10 nm to 1 gM) antagonised the BD-737(100 nM)-induced effect ( Figure 6). …”

“…Although the different profiles of action of these specific a drugs were most likely due to methodological differences between protocols, the observation by Gonzalez-Alvear & Werling (1995) supported the notion that (+)-pentazocine and BD-737, and DTG were acting on a1 and a2 receptors, respectively. They also showed that the BD-737-induced modulation of the (BD-737 and BD-738;de Costa et al, 1990;Bowen et al, 1992), N-[2-(3,4- 1993), N,N-dipropyl -2 -[4-methoxy-3-(21 lphenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) (Okuyama et al, 1993) and 4 -(4 -chlorophenyl) -a -4 -fluorophenyl) -4 -hydroxy -1-piperidinebutanol (reduced haloperidol; Bowen et al, 1990; Klein et al, 1994) has been proposed to behave as an antagonist in some systems and as an agonist in others Klein et al, 1994 Fink et al, 1989). At the end of the experiments, the hippocampal slices were collected and solubilised in 0.5 ml of Soluene' 350 (Packard Instruments, Rungis, France) and the radioactivity in the slices and superfusate samples was determined by liquid scintillation spectrometry (Packard Tris-Carb 4660).…”