Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling and mutagenesis studies revealed that the selectivity of NAQ for MOR is because of the π-π stacking of the isoquinoline ring of NAQ with W318.
Therefore, other heterocyclic ring systems were explored to obtain a diverse library of compounds with similar or different molecular interactions and pharmacologic characteristics as NAQ. The newly designed compounds were indole analogs of 6α/β-naltrexamine. The compounds were synthesized and the affinity and selectivity for MOR determined using the radioligand binding assay while the functional activity at MOR was determined using the [35S]GTPγS binding assay. The indole analog of 6α-naltrexamine substituted at position 7 (compound 6) was found to be very potent and had the lowest efficacy in the [35S]GTPγS functional assay while the indole analog of 6β-naltrexamine substituted at position 2 (compound 10) was identified as a MOR agonist and had the greatest efficacy. In vivo studies were conducted using the warm-water immersion assay to find whether the synthesized compounds had antinociceptive effects and/or blocked the antinociceptive effects of morphine. Not surprisingly, compound 10 was identified as an opioid agonist while compound 6 almost completely blocked morphine’s antinociceptive effects. The opioid antagonist effect of compound 6 was found to be dose dependent with an AD50 of 2.39 mg/kg (0.46-12.47). An opioid withdrawal assay was conducted on compound 6 using morphine-pelleted mice. Compound 6 produced significantly less withdrawal symptoms at 50 mg/kg than naltrexone at 1 mg/kg. Therefore, compound 6 has the potential to be used in opioid addiction and withdrawal treatment.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-5925 |
| Date | 01 January 2017 |
| Creators | Obeng, Samuel |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © Samuel Obeng |
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