Interactions of chloroquine with benzodiazepine, γ-aminobutyric acid and opiate receptors

Liu, Linda; Katz, Yeshayahu; Weizman, Ronit; Rosenberg, B; Pasternak, Gavril W.; Gavish, Moshe

doi:10.1016/0006-2952(91)90574-o

Cited by 14 publications

(7 citation statements)

References 10 publications

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“…Our proposal of the opiate action of chloroquine receives support from reports that chloroquine is employed by drug addicts on the streets in conjunction with heroin (adulteration) without loss of efficacy, 21 and that chloroquine may interact with opiate receptors centrally in rats 22 . Our previous finding, however, indicates that placebo provides no prevention of chloroquine‐itching in proven malaria (0% protection rate) 4 …”

Section: Discussionsupporting

confidence: 55%

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

2004

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Naltrexone exerted an antipruritic action, at least to a similar extent to promethazine in patients with chloroquine-induced itching in malaria fever. However, the relationship between parasite density and resultant pruritus was significantly different between naltrexone and promethazine. Thus, micro-opiate receptors/and or endogenous opioids may contribute to chloroquine itching in malaria fever, in humans, in accord with animal experimental findings. Malaria parasite density in blood is a strong determinant of itching severity in patients predisposed to chloroquine-induced pruritus.

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Section: Discussionsupporting

confidence: 55%

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

2004

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“…Interestingly, at heteromeric 5‐HT 3 receptors, chloroquine and mefloquine displayed properties similar to those at homomeric receptors, but quinine had effects that were consistent with non‐competitive inhibition. Similarities in the actions of these compounds at 5‐HT 3A , GABA A and nACh receptors suggest the possibility of conserved sites of action for these compounds ( Liu et al , 1991 ; Sieb et al , 1996 ; Ballestero et al , 2005 ; Thompson and Lummis, 2007a ). For the compounds that showed competitive behaviour, our ligand docking provides further evidence for this.…”

Section: Discussionmentioning

confidence: 98%

Antimalarial drugs inhibit human 5‐HT₃ and GABA_A but not GABA_C receptors

Thompson¹,

Lummis²

2008

British J Pharmacology

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Background and purpose: Antimalarial compounds have been previously shown to inhibit rodent nicotinic acetylcholine (nACh) and 5-HT 3 receptors. Here, we extend these studies to include human 5-HT 3A , 5-HT 3AB , GABA A a1b2, GABA A a1b2g2 and GABA C r1 receptors. Experimental approach: We examined the effects of quinine, chloroquine and mefloquine on the electrophysiological properties of receptors expressed in Xenopus oocytes. Key results: 5-HT 3A receptor responses were inhibited by mefloquine, quinine and chloroquine with IC 50 values of 0.66, 1.06 and 24.3 mM. At 5-HT 3AB receptors, the potencies of mefloquine (IC 50 ¼ 2.7 mM) and quinine (15.8 mM), but not chloroquine (23.6 mM), were reduced. Mefloquine, quinine and chloroquine had higher IC 50 values at GABA A a1b2 (98.7, 0.40 and 0.46 mM, respectively) and GABA A a1b2g2 receptors (0.38, 1.69 and 0.67 mM, respectively). No effect was observed at GABA C r1 receptors. At all 5-HT 3 and GABA A receptors, chloroquine displayed competitive behaviour and mefloquine was non-competitive. Quinine was competitive at 5-HT 3A and GABA A receptors, but non-competitive at 5-HT 3AB receptors. Homology modelling in combination with automated docking suggested orientations of quinine and chloroquine at the GABA A receptor binding site. Conclusions and implications:The effects of mefloquine, quinine and chloroquine are distinct at GABA A and GABA C receptors, whereas their effects on 5-HT 3AB receptors are broadly similar to those at 5-HT 3A receptors. IC 50 values for chloroquine and mefloquine at 5-HT 3 receptors are close to therapeutic blood concentrations required for malarial treatment, suggesting that their therapeutic use could be extended to include the treatment of 5-HT 3 receptor-related disorders.

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“…The evidence that chloroquine toxicity might be mediated through interactions with the benzodiazepine-receptor complex is, however, inconclusive. Whereas Liu reported that chloroquine has a low affinity for -y-aminobutyric acid and benzodiazepine receptors [9], other workers have shown that some synthetic quinoline derivatives do selectively inhibit diazepam binding to certain benzodiazepine receptors [10]. These compounds have no sedative or anticonvulsant activities.…”

Section: Discussionmentioning

confidence: 99%

Diminished sedation during diazepam treatment for chloroquine intoxication

Croes¹,

Augustijns²,

Sabbé³

et al. 1993

Pharm World Sci

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We report a case of a woman hospitalized after chloroquine overdose whose whole blood concentration on admission was 7.87 micrograms/ml. High blood concentrations of chloroquine induce cardiotoxicity and have been associated with death when they exceed 3.0 micrograms/ml. Early administration of massive doses of diazepam has been described to reduce the mortality due to chloroquine toxicity, but the protective mechanism has remained unknown. This patient was treated with diazepam (2.0 mg/kg over 30 min followed by a dosage of 1.0 to 2.0 mg/kg over 24 h), yet she remained awake despite the high plasma concentrations of diazepam and nordiazepam which would normally be associated with sedation. This suggests an antagonistic effect of chloroquine on the benzodiazepine-induced sedation due to an interaction between these drugs at their site of action.

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Interactions of chloroquine with benzodiazepine, γ-aminobutyric acid and opiate receptors

Cited by 14 publications

References 10 publications

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

Antimalarial drugs inhibit human 5‐HT₃ and GABA_A but not GABA_C receptors

Diminished sedation during diazepam treatment for chloroquine intoxication

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Interactions of chloroquine with benzodiazepine, γ-aminobutyric acid and opiate receptors

Cited by 14 publications

References 10 publications

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

Endogenous opioids, µ‐opiate receptors and chloroquine‐induced pruritus: A double‐blind comparison of naltrexone and promethazine in patients with malaria fever who have an established history of generalized chloroquine‐induced itching

Antimalarial drugs inhibit human 5‐HT3 and GABAA but not GABAC receptors

Diminished sedation during diazepam treatment for chloroquine intoxication

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Antimalarial drugs inhibit human 5‐HT₃ and GABA_A but not GABA_C receptors