Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity

Abstract

Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.

Penfluridol as a Candidate of Drug Repurposing for Anticancer Agent

“…Recently, measured binding affinity values, Ki (nM), for central nervous system G protein coupled receptors (GPCRs) and transporters related to the efficacy and side effects of penfluridol were 356 (5-hydroxytryptamine [serotonin] receptor 1A; 5HT 1A ), 3560 (5HT 1D ), 361 (5HT 2A ), 184 (5HT 2B ), 881 (5HT 2C ), 10,000 (5HT 5A ), 10,000 (5HT 6 ), 280 (5HT 7 ), 147 (dopamine receptor D1), 159 (D 2 ), 136 (D 3 ), 10,000 (D 4 ), 125 (D 5 ), 10,000 (κ-opioid receptor), 867 (μ-opioid receptor), 1714 (δ-opioid receptor), 10,000 (histamine receptor 1 H 1 ), 10,000 (H 2 ), 588 (norepinephrine transporter), 10,000 (serotonin transporter), 1714 (dopamine transporter), 602 (α 1D -adrenoreceptor), 401 (α 2B ), 455 (α 2C ), and 515 nM (β 3 ) [9]. These values were reported by Ashraf-Uz-Zamanem et al [9] and supported by the National Institute of Mental Health’s Psychoactive Drug Screening Program. In particular, the Ki values of 184 (5HT 2B ), 147 (D 1 ), 159 (D 2 ), 136 (D 3 ), and 125 nM (D 5 ) seem to be more significant.…”

“…It is difficult to find a report explaining various mechanisms of anticancer activity involving of D 2 -receptor antagonism. In addition, penfluridol derivatives showed distinct anticancer and antipsychotic activities, thus suggesting that D 2 -receptor antagonism may or may not contribute to the anticancer activity of penfluridol [9].…”

“…The dose used as an anticancer agent is 50 mg/day, which is significantly higher than the dose administered once weekly as an antipsychotic agent [9]. Therefore, neurological side effects such as epilepsy, fatigue, dyskinesias, parkinsonism, akathisia, dystonia and depression, which are observed in antipsychotic drug doses, are more likely to occur when the higher doses associated with anticancer therapy are used.…”

“…Therefore, in the development of new penfluridol derivatives as anticancer drugs, some of the antipsychotic effects of the compounds were reduced and some of the anticancer effects enhanced (Figure 4). Ashraf-Uz-Zaman et al [9] first suggested the possibility of deriving penfluridol derivatives with such characteristics.…”

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis

“…This leads to one of the important elements of this study, which was the low dose of penfluridol in the in vitro, and also in the in vivo experiments. The penfluridol dose prescribed for chronic schizophrenia and similar psychotic disorders ranges from 60 to 140 mg weekly, with most studies having an average dose of 80 mg [23,24,58]. The oral administration of 1 mg/kg dose in mice corresponds to only 39 mg/week of human dose, which, according to allometric dose scaling based on body surface area [59], is half of the average weekly dose prescribed to schizophrenia patients.…”