Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine

Gilbert, Annie-Kim; Hosztafi, Sándor; Mahurter, Loriann; Pasternak, Gavril W.

doi:10.1016/j.ejphar.2004.03.050

Cited by 16 publications

(7 citation statements)

References 41 publications

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“…These receptors belong to the superfamily of seven transmembrane spanning receptors that couple to G-proteins (Chen et al, 1993), but some studies have suggested that heroin and morphine may act by differential mechanisms (Rady et al, 1991), and suggest the possibility that an alternative splice variant of the cloned mu opioid receptor may be responsible for the analgesic actions of heroin (Gilbert et al, 2004;Schuller et al, 1999). Chronic heroin use produces high levels of tolerance and physical dependence, but the biological mechanisms, which mediate these effects in brain, are still not clear.…”

Section: Introductionmentioning

confidence: 98%

Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration

2005

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Section: Introductionmentioning

confidence: 98%

Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration

2005

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“…It has also been reported that one of heroin metabolites, 6-MAM, possesses higher efficacy than other heroin metabolites at mu-opioid receptors, which may contribute to the higher efficacy of heroin compared with morphine in certain behavioral paradigms in vivo (Selley et al, 2001). And systemically administrated heroin and its active metabolite, 6-MAM, were significantly more potent than all the other derivatives, including morphine in analgesic test (Gilbert et al, 2004). These above reports seem to give us the hint that heroin metabolites, especially the 6-MAM, might be mainly responsible for the differential effect between morphine and heroin.…”

Section: Discussionmentioning

confidence: 75%

“…Antioligodeoxynucleotides targeting exon 2 of the MOR-1 gene can decrease heroin and M6G analgesia, but not morphine (Rossi et al, 1996), and, conversely, the deletion of exon 1 effectively lowers morphine analgesia but has no effect on heroin and M6G (Matthes et al, 1996;Schuller et al, 1999). Finally, heroin and morphine show an incomplete cross-tolerance owing to the maintenance of heroin analgesic activity in a mouse model of morphine tolerance (Lange et al, 1980;Rossi et al, 1996;Gilbert et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Morphine and Heroin Differentially Modulate In Vivo Hippocampal LTP in Opiate-Dependent Rat

Bao

Kang

et al. 2007

Neuropsychopharmacol

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Addictive drugs have been shown to severely influence many neuronal functions, which are considered as the underlying mechanisms for physiological and psychological dependences. We previously showed that in vivo LTP in rat hippocampal CA1 region is significantly reduced during withdrawal following chronic opiates treatment, and the reduced LTP can be restored by re-exposure of animals to corresponding drugs. Here, we further demonstrated that during opiates withdrawal, the re-exposure of morphine either systemically (subcutaneously) or locally (intracerebroventricularly) could restore the reduced LTP in heroin-dependent rats, but heroin could not restore the reduced LTP, in morphine-dependent rats, indicating differential modulations of hippocampal functions by those two opiates. In contrast, DAMGO, a mu-opioid receptor (MOR) agonist, could restore the reduced LTP, and CTOP, a MOR antagonist, could block the restoration in rats dependent on both opiates, showing that MOR is functional under such conditions. However, the upregulation of hippocampal PKA activity during morphine withdrawal could be suppressed by re-exposure of morphine but not that of heroin, suggesting a likely underlying mechanism of the differential modulation of LTP by two opiates. Taken together, our study clearly demonstrates that chronic abuse of opiates inevitably leads to severe alteration of hippocampal LTP, and reveals the interesting differences between morphine and heroin in their effects on the differential modulation of hippocampal synaptic plasticity.

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“…In general, previous work in the literature does not provide a good framework to rationalize the effect of modifying positions 7 and 8. Reduction of the 7,8 double bond in morphine, leading to dihydromorphine, increases activity approximately by two fold at the DOR and MOR, but decreases it at the KOR by 8-fold [53][54][55]. When comparing dihydrocodeine to codeine (8), the activity is in contrast decreasing at DOR and KOR (respectively 6-and 2-fold) and increasing 8.5-fold at MOR [56].…”

Section: Structure-activity Relationshipsmentioning

confidence: 97%

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

Ahonen

Rinne

Grutschreiber

et al. 2018

European Journal of Medicinal Chemistry

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Despite extensive years of research, the direct oxidation of the 7,8-double bond of opioids has so far received little attention and knowledge about the effects of this modification on activity at the different opioid receptors is scarce. We herein report that potassium permanganate supported on iron(II) sulfate heptahydrate can be used as a convenient oxidant in the one-step, heterogeneous conversion of Δ-opioids to the corresponding 7β-hydroxy-8-ketones. Details of the reaction mechanism are given and the effects of the substituent at position 6 of several opioids on the reaction outcome is discussed. The opioid hydroxy ketones prepared are antagonists at the mu- and delta-opioid receptors. Docking simulations and detailed structure-activity analysis revealed that the presence of the 7β-hydroxy-8-ketone functionality in the prepared compounds can be used to gain activity towards the delta opioid receptor. The 7β-hydroxy-8-ketones prepared with this method can also be regarded as versatile intermediates for the synthesis of other opioids of interest.

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Pharmacological characterization of dihydromorphine, 6-acetyldihydromorphine and dihydroheroin analgesia and their differentiation from morphine

Cited by 16 publications

References 41 publications

Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration

Mechanisms of mu opioid receptor/G-protein desensitization in brain by chronic heroin administration

Morphine and Heroin Differentially Modulate In Vivo Hippocampal LTP in Opiate-Dependent Rat

Synthesis of 7β-hydroxy-8-ketone opioid derivatives with antagonist activity at mu- and delta-opioid receptors

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