The Clinical Significance of Halopemide, a Dopamine-Blocker Related to the Butyrophenones

Abstract

The resocializing and activating properties of halopemide were investigated in an open study and a double-blind study in 20 patients who had been hospitalized on account of various psychiatric disorders. The results of the open study showed a significant improvement in contact and activity, regardless of the nosological characteristics. There was no significant difference in therapeutic effect between the single (2 x 10 mg/day) and the double (2 × 20 mg/day) dose. The patients were more approachable, sought contact with their surroundings and showed a greater interest in their work. However, these results were not confirmed by the double-blind study, which for these target symptoms showed no significant difference between the placebo phase and halopemide phase. Two factors that might explain the discrepancy between the results of the open study and the double-blind study are postulated: the difference in experimental methods and the short duration of the study phases.

Amyotrophic Lateral Sclerosis Modifiers inDrosophilaReveal the Phospholipase D Pathway as a Potential Therapeutic Target

“…Two PLD inhibitors are currently available; one is halopemide, which was developed as a neuropsychiatric drug ( Bruntz et al 2014 ; Zhang and Frohman 2014 ). In limited clinical trials, halopemide had no reported side effects at doses sufficiently high enough to fully block PLD activity ( De Cuyper et al 1984 ). This indicates that PLD inhibition does not cause major toxicity, even over prolonged periods of time.…”

Drugs for Allosteric Sites on Receptors

“…Halopemide, a dopamine antagonist (D 2 pIC 50 = 7), also potently inhibits both PLD1 (IC 50 = 21 nM) and PLD2 (IC 50 = 300 nM) (52); however, like most atypical antipsychotics, it possesses several off-target effects. In clinical trials with halopemide that achieved exposures whereby both PLD isozymes were inhibited, no adverse events were noted and all biochemistry was normal, suggesting that inhibition of PLD in humans is well tolerated and safe (53). On the basis of the conformational flexibility of the PLD enzymes, the presence of a PH domain, and the piperidine benzimidazolone moiety, halopemide ( 15 ) was reminiscent of the chemotype 7 (Figure 3 c ) that engendered allosteric Akt kinase inhibition (39).…”

The phospholipase D superfamily as therapeutic targets

“…Intriguingly, halopemide, which was developed for its dopamine receptor blocking ability and hence use in psychosis, was used clinically at a sufficiently high dose to fully block PLD activity [36], suggesting that PLD inhibition does not cause major unacceptable toxicity even over prolonged periods of time. This observation parallels findings for the PLD1 and 2 single- and double-knockout mice which are viable and overtly normal to inspection [33], indicating that PLD activity is generally dispensable and hence that pharmacological inhibition has a reasonable chance of being tolerated in the short-term and potentially even in the long-term, with caveats as discussed subsequently.…”