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. 2017 Feb 1;27(3):666-669.
doi: 10.1016/j.bmcl.2016.11.057. Epub 2016 Nov 22.

Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands

Jason R Healy  1 , Padmavani Bezawada  2 , Nicholas W Griggs  3 , Andrea L Devereaux  4 , Rae R Matsumoto  5 , John R Traynor  3 , Andrew Coop  2 , Christopher W Cunningham  6
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Benzylideneoxymorphone: A new lead for development of bifunctional mu/delta opioid receptor ligands

Jason R Healy et al. Bioorg Med Chem Lett. .

Abstract

Opioid analgesic tolerance remains a considerable drawback to chronic pain management. The finding that concomitant administration of delta opioid receptor (DOR) antagonists attenuates the development of tolerance to mu opioid receptor (MOR) agonists has led to interest in producing bifunctional MOR agonist/DOR antagonist ligands. Herein, we present 7-benzylideneoxymorphone (6, UMB 246) displaying MOR partial agonist/DOR antagonist activity, representing a new lead for designing bifunctional MOR/DOR ligands.

Keywords: Analgesic tolerance; Benzylideneoxymorphone; Delta opioid receptor; Mu opioid receptor; Oxymorphone.

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Figures

Figure 1
Figure 1
Three examples of small-molecule, bifunctional MOR agonist/DOR antagonist lead molecules.-
Figure 2
Figure 2
Schematic describing the “message-address” rationale for designing bifunctional MOR agonist/DOR antagonist probes based on modification of oxymorphone. CPM = cyclopropylmethyl.
Figure 3
Figure 3
Acute dose- and time-response curves for s.c. 6 treatment for the hot plate assay. For details, see . Significance relative to saline control: * p<0.05. ** p<0.01. *** p<0.001.
Figure 4
Figure 4
Acute dose- and time-response curves for s.c. 6 treatment for the tail-flick assay. For details, see . Significance relative to saline control: ** p<0.01. *** p<0.001.
Scheme 1
Scheme 1
Synthesis of 6-8. Reagents and Conditions: i) BBr3, CHCl3, 0°C, 30 min; NH4OH(aq), 0°C, 30 min. ii) Ac2O, reflux, 24 hr; 1-chloroethyl chloroformate, K2CO3, Cl(CH2)2Cl, reflux, 24 hr; NaOH, MeOH, reflux, 3 hr. iii) R-Br, K2CO3, RT, 24 hr. iv) PhCHO, NaOH, MeOH, 0°C, 18 hr.
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