Mixed κ agonists and μ agonists/Antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan

Neumeyer, John L.; Gu, Xiaoxia; Vliet, L.A. van; DeNunzio, Nicholas J.; Rusovici, Daniela E.; Cohen, Dana J.; Negus, S. Stevens; Mello, Nancy K.; Bidlack, Jean M.

doi:10.1016/s0960-894x(01)00543-1

Cited by 28 publications

(25 citation statements)

References 31 publications

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“…Based on its ability to inhibit HIV-1 expression in CD4+ lymphocytes, Peterson and coworkers have proposed that naltrexone be used as an adjunctive therapy to HAART in the treatment of HIV . Alternatively, mixed KOR agonists and MOR agonists/antagonists have been proposed as beneficial in the treatment of addiction and pain Neumeyer et al, 2001), and may also be beneficial in treating neuroAIDS. MOR antagonists in particular should be beneficial; since we find that opiate synergism with HIV toxicity is almost exclusively mediated through MOR.…”

Section: Opiate Hiv Interactions In Glial Precursorsmentioning

confidence: 99%

Molecular targets of opiate drug abuse in neuro AIDS

et al. 2005

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Opiate drug abuse, through selective actions at mu-opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiates drugs have some affinity for kappa (KOR) and/or delta (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS.

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Section: Opiate Hiv Interactions In Glial Precursorsmentioning

confidence: 99%

Molecular targets of opiate drug abuse in neuro AIDS

et al. 2005

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“…Increasing evidence suggests that κ agonists with mixed activity at κ and µ receptors may be more promising candidates for drug abuse pharmacotherapy than highly selective κ agonists [14,15] . Therefore, one potential treatment strategy for opioid addiction is to develop compounds with mixed activity at κ and µ receptors [16,17] . A recent study from our group demonstrated that ATPM, a novel mixed κ agonist and μ agonist/ antagonist, can reduce heroin self-administration with relatively low levels of sedation [18] .…”

Section: Introductionmentioning

confidence: 99%

Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice

Sun

Wang

et al. 2010

Acta Pharmacol Sin

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Aim: To investigate the effects of ATPM-ET -N-cyclopropylmethylmorphinan hydrochloride] on physical dependence and behavioral sensitization to morphine in mice. Methods: The pharmacological profile of ATPM-ET was characterized using competitive binding and GTPγS binding assays. We then examined the antinociceptive effects of ATPM-ET in the hot plate test. Morphine dependence assay and behavioral sensitization assay were used to determine the effect of ATPM-ET on physical dependence and behavior sensitization to morphine in mice. Results: The binding assay indicated that ATPM-ET ATPM-ET exhibited a high affinity to both κ-and µ-opioid receptors with K i values of 0.15 nmol/L and 4.7 nmol/L, respectively, indicating it was a full κ-opioid receptor agonist and a partial μ-opioid receptor agonist. In the hot plate test, ATPM-ET produced a dose-dependent antinociceptive effect, with an ED 50 value of 2.68 (2.34-3.07) mg/kg. Administration of ATPM-ET (1 and 2 mg/kg, sc) prior to naloxone (3.0 mg/kg, sc) injection significantly inhibited withdrawal jumping of mice. In addition, ATPM-ET (1 and 2 mg/kg, sc) also showed a trend toward decreasing morphine withdrawal-induced weight loss. ATPM-ET (1.5 and 3 mg/kg, sc) 15 min before the morphine challenge significantly inhibited the morphine-induced behavior sensitization (P<0.05). Conclusion: ATPM-ET may have potential as a therapeutic agent for the treatment of drug abuse.

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“…The highly potent (−)-3-hydroxy-N-( E )-iodoallylmorphinan14 suggested the replacement of the N-cyclopropylmethyl group in cyclorphan with a fluoropropyl group to make compounds 7c and its analogs 9c, 11, 13c, and 19c , and introduced a trifluoroethyl substituent to the amino group of the aminothiazole component in 3 to make compound 15 (Scheme 1 and Scheme 2). …”

Section: Introductionmentioning

confidence: 99%

Aminothiazolomorphinans with Mixed κ and μ Opioid Activity

et al. 2011

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A series of N-substituted and N′-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower than their prototype aminothiazolo-Ncyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [ 35 S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N′-monosubstituted aminothiazolederived morphinans may be valuable for the development of drug abuse medications.

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Mixed κ agonists and μ agonists/Antagonists as potential pharmacotherapeutics for cocaine abuse: synthesis and opioid receptor binding affinity of N-substituted derivatives of morphinan

Cited by 28 publications

References 31 publications

Molecular targets of opiate drug abuse in neuro AIDS

Molecular targets of opiate drug abuse in neuro AIDS

Effects of ATPM-ET, a novel κ agonist with partial μ activity, on physical dependence and behavior sensitization in mice

Aminothiazolomorphinans with Mixed κ and μ Opioid Activity

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