A Novel µ-Opioid Receptor Ligand with High In Vitro and In Vivo Agonist Efficacy

Lackó, Erzsébet; Váradi, András; Rapavi, R.; Zádor, Ferenc; Riba, Pál; Benyhe, Sándor; Borsodi, Anna; Hosztafi, Sándor; Tı́már, József; Noszál, Béla; Fürst, S.; Al-Khrasani, Mahmoud

doi:10.2174/092986712803306376

Cited by 21 publications

(44 citation statements)

References 44 publications

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“…All reference compounds performed adequately ( Fig. 4A and C, Table 2) and were correspondent with previous results (Lacko et al, 2012). According to the results in rat brain membrane homogenates 14-Omethylmorphine dose dependently increased […”

Section: Agonist Activity Measurements In [ 35 S]gtpγs Binding Assayssupporting

confidence: 89%

“…In the binding assays all radioligand's total specific binding was reduced by their own unlabeled homologous ligand with a K i value in the nanomolar range (Table 1), which indicates the adequate performance and selectivity of the radioligands and are in accordance with previous data (Lacko et al, 2012).…”

Section: Binding Affinity Measurements In Radioligand Competition Binsupporting

confidence: 86%

“…14-O-methylmorphine was synthesized as described previously (Lacko et al, 2012). Briefly, 14-OH-codeinone was used as the starting material (Fig.…”

Section: Chemistrymentioning

confidence: 99%

“…The experimental paradigm was similar as described previously (Lacko et al, 2012). Briefly, after the equilibration time (30-40 min and 90-120 min for mouse vas deferens and rat vas deferens respectively) the first dose of agonist was added and the concentration-effect curves were constructed in a cumulative manner.…”

Section: Experimental Paradigms Of Mouse and Rat Vas Deferensmentioning

confidence: 99%

“…14-methoxy analogues of oxymorphone (14-O-methyloxymorphone) or morphine-6-O-sulfate have been reported to have higher affinity for opioid receptors and enhanced antinociceptive action compared to the parent compounds (Fürst et al, 2005;Khalefa et al, 2013;Lacko et al, 2012;Spetea et al, 2004). To the best of our knowledge, the in vitro and in vivo pharmacological profile of 14-methoxy analogues of morphine, particularly, 14-O-methylmorphine ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Zádor

Balogh

Váradi

et al. 2017

European Journal of Pharmacology

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A B S T R A C T14-O-methyl (14-O-Me) group in morphine-6-O-sulfate (M6SU) or oxymorphone has been reported to be essential for enhanced affinity, potency and antinociceptive effect of these opioids. Herein we report on the pharmacological properties (potency, affinity and efficacy) of the new compound, 14-O-methylmorphine (14-OMeM) in in vitro. Additionally, we also investigated the antinociceptive effect of the novel compound, as well as its inhibitory action on gastrointestinal transit in in vivo. binding. In addition, 14-O-MeM compared to morphine showed higher affinity for μ-opioid receptor (MOR). In vivo, in rat tail-flick test 14-O-MeM proved to be stronger antinociceptive agent than morphine after peripheral or central administration. Additionally, both compounds inhibited the gastrointestinal peristalsis. However, when the antinociceptive and antitransit doses for each test compound are compared, 14-O-MeM proved to have slightly more favorable pharmacological profile. Our results affirm that 14-O-MeM, an opioid of high efficacy and affinity for MOR can be considered as a novel analgesic agent of potential clinical value.

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Section: Agonist Activity Measurements In [ 35 S]gtpγs Binding Assayssupporting

confidence: 89%

Section: Binding Affinity Measurements In Radioligand Competition Binsupporting

confidence: 86%

“…14-O-methylmorphine was synthesized as described previously (Lacko et al, 2012). Briefly, 14-OH-codeinone was used as the starting material (Fig.…”

Section: Chemistrymentioning

confidence: 99%

Section: Experimental Paradigms Of Mouse and Rat Vas Deferensmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

Zádor

Balogh

Váradi

et al. 2017

European Journal of Pharmacology

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The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats

et al. 2018

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Opioid analgesics devoid of central side effects are unmet medical need in the treatment of acute pain (e.g. post-operative pain). Recently, we have reported on 14-O-methylmorphine-6-O-sulfate (14-O-MeM6SU), a novel opioid agonist of high efficacy producing peripheral antinociception in subchronic inflammatory pain in certain doses. The present study focused on the antinociceptive effect of 14-O-MeM6SU compared to morphine in formalin test of an early/acute (Phase I) and late/tonic (Phase II) pain phases. Subcutaneous 14-O-MeM6SU (253-1012 nmol/kg) and morphine (3884-31075 nmol/kg) dose dependently reduced the pain behaviors of both phases. Co-administered naloxone methiodide (NAL-M), a peripherally acting opioid antagonist, abolished the antinociceptive effect of 506 nmol/kg 14-O-MeM6SU. On the other hand, the effects of 14-O-MeM6SU (1012 nmol/kg) and morphine (15538 nmol/kg) were only partially affected by NAL-M, indicating the contribution of CNS to antinociception. Locally injected test compounds into formalin treated paws caused antinociception in both phases. Locally effective doses of test compounds were also injected into contralateral paws. Morphine showed effects in both phases, 14-O-MeM6SU in certain doses failed to produce antinociception in either phase. A NAL-M reversible systemic dose of 14-O-MeM6SU and the lowest systemic effective dose of morphine were evaluated for their sedative effects following isoflurane-induced sleeping (righting reflex). In contrast to morphine, 14-O-MeM6SU in certain antinociceptive doses showed no impact on sleeping time. These data highlight that high efficacy opioids of limited CNS penetration in certain doses mitigate somatic and inflammatory pain by targeting MOR at the periphery.

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The Pharmacological Effects of Phenylephrine are Indirect, Mediated by Noradrenaline Release from the Cytoplasm

et al. 2022

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Phenylephrine (PE) is a canonical α1-adrenoceptor-selective agonist. However, unexpected effects of PE have been observed in preclinical and clinical studies, that cannot be easily explained by its actions on α1-adrenoceptors. The probability of the involvement of α2- and β-adrenoceptors in the effect of PE has been raised. In addition, our earlier study observed that PE released noradrenaline (NA) in a [Ca2+]o-independent manner. To elucidate this issue, we have investigated the effects of PE on [3H]NA release and α1-mediated smooth muscle contractions in the mouse vas deferens (MVD) as ex vivo preparation. The release experiments were designed to assess the effects of PE at the presynaptic terminal, whereas smooth muscle isometric contractions in response to electrical field stimulation were used to measure PE effect postsynaptically. Our results show that PE at concentrations between 0.3 and 30 µM significantly enhanced the resting release of [3H]NA in a [Ca2+]o-independent manner. In addition, prazosin did not affect the release of NA evoked by PE. On the contrary, PE-evoked smooth muscle contractions were inhibited by prazosin administration indicating the α1-adrenoceptor-mediated effect. When the function of the NA transporter (NAT) was attenuated with nisoxetine, PE failed to release NA and the contractions were reduced by approximately 88%. The remaining part proved to be prazosin-sensitive. The present work supports the substantial indirect effect of PE which relays on the cytoplasmic release of NA, which might explain the reported side effects for PE.

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A Novel µ-Opioid Receptor Ligand with High In Vitro and In Vivo Agonist Efficacy

Cited by 21 publications

References 44 publications

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

14-O-Methylmorphine: A Novel Selective Mu-Opioid Receptor Agonist with High Efficacy and Affinity

The Peripheral Versus Central Antinociception of a Novel Opioid Agonist: Acute Inflammatory Pain in Rats

The Pharmacological Effects of Phenylephrine are Indirect, Mediated by Noradrenaline Release from the Cytoplasm

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