2018
DOI: 10.1021/acschemneuro.8b00234
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Abstract: Two 6β- N-heterocyclic naltrexamine derivatives, NAP and NMP, have been identified as peripherally selective mu opioid receptor (MOR) antagonists. To further enhance the peripheral selectivity of both compounds, the 17-amino group and the nitrogen atom of the pyridine ring in both NAP and NMP were methylated to obtain dMNAP and dMNMP, respectively. Compared with NAP and NMP, the binding affinities of dMNAP and dMNMP shifted to MOR and KOR (kappa opioid receptor) dual selective and they acted as moderate effica… Show more

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Cited by 6 publications
(3 citation statements)
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References 64 publications
(128 reference statements)
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“…The molecular docking studies were conducted by using GOLD 5.6. Similar to the studies of the epoxymorphinan analogues developed in our group, ,, D 3.32 in the MOR and KOR may form ionic interactions with the protonated nitrogen atom at the 17-amino group of nalfurafine and 42B. Y 3.33 in the MOR and KOR may form hydrogen bonding interactions with the dihydrofuran oxygen atom of both ligands.…”
Section: Materials and Methodssupporting
confidence: 68%
“…The molecular docking studies were conducted by using GOLD 5.6. Similar to the studies of the epoxymorphinan analogues developed in our group, ,, D 3.32 in the MOR and KOR may form ionic interactions with the protonated nitrogen atom at the 17-amino group of nalfurafine and 42B. Y 3.33 in the MOR and KOR may form hydrogen bonding interactions with the dihydrofuran oxygen atom of both ligands.…”
Section: Materials and Methodssupporting
confidence: 68%
“…Thus, the epoxymorphinan moiety (“message” portion) interacted with the “message” domain; the indole ring (“address” portion) interacted with the “address” domain, which was similar to other reported opioid ligands. 7173 In the MOR_NAN complex, the “message” portion of NAN formed ionic interaction with D147 3.32 , hydrogen bonding interaction with Y148 3.33 , and hydrophobic interactions with residues M151 3.36 , W293 6.48 , and H297 6.52 . Meanwhile, the “address” portions of NAN formed hydrophobic interactions with the “address” domain of the MOR, formed by residues L219 ECL2 , F221 ECL2 , E229 5.35 , L232 5.38 , and K233 5.39 (Figure 10C and Table 4).…”
Section: ■ Results and Discussionmentioning
confidence: 99%
“…Our laboratories have been engaged in identifying novel chemical entities toward developing selective opioid receptor ligands by employing the “message-address concept” . Our drug design efforts have led to the development of a small molecule library encompassing different substituents on the epoxymorphinan skeleton. Previously, we reported a highly selective MOR antagonist 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)­carboxamido]­morphinan (NAP), which showed high binding affinity for the MOR and at least 500-fold and 150-fold selectivity over the DOR and KOR in vitro, respectively. , However, further in vivo pharmacological characterization of NAP revealed that it showed limited potency with an AD 50 of 4.51 (95% CL, 2.45–8.20) mg/kg, in part because of its constrained ability to penetrate the blood–brain barrier (BBB), making NAP a peripherally acting selective MOR antagonist. , Collectively, this data encouraged us to explore NAP as a lead for centrally acting MOR-selective antagonists with potential to treat OUD. Herein, we report our efforts toward developing centrally acting MOR antagonists by applying an isosteric replacement as a lead optimization strategy.…”
Section: Introductionmentioning
confidence: 99%