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. 2020 Jun 6;25(11):2640.
doi: 10.3390/molecules25112640.

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments

Meining Wang  1 , Thomas C Irvin  1 , Christine A Herdman  1 , Ramsey D Hanna  1 , Sergio A Hassan  2 , Yong-Sok Lee  2 , Sophia Kaska  3 , Rachel Saylor Crowley  3 , Thomas E Prisinzano  3 , Sarah L Withey  4 , Carol A Paronis  4 , Jack Bergman  4 , Saadet Inan  5 , Ellen B Geller  5 , Martin W Adler  5 , Theresa A Kopajtic  6 , Jonathan L Katz  6 , Aaron M Chadderdon  7 , John R Traynor  7 , Arthur E Jacobson  1 , Kenner C Rice  1
Affiliations

The Intriguing Effects of Substituents in the N-Phenethyl Moiety of Norhydromorphone: A Bifunctional Opioid from a Set of "Tail Wags Dog" Experiments

Meining Wang et al. Molecules. .

Abstract

(-)-N-Phenethyl analogs of optically pure N-norhydromorphone were synthesized and pharmacologically evaluated in several in vitro assays (opioid receptor binding, stimulation of [35S]GTPγS binding, forskolin-induced cAMP accumulation assay, and MOR-mediated β-arrestin recruitment assays). "Body" and "tail" interactions with opioid receptors (a subset of Portoghese's message-address theory) were used for molecular modeling and simulations, where the "address" can be considered the "body" of the hydromorphone molecule and the "message" delivered by the substituent (tail) on the aromatic ring of the N-phenethyl moiety. One compound, N-p-chloro-phenethynorhydromorphone ((7aR,12bS)-3-(4-chlorophenethyl)-9-hydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 2i), was found to have nanomolar binding affinity at MOR and DOR. It was a potent partial agonist at MOR and a full potent agonist at DOR with a δ/μ potency ratio of 1.2 in the ([35S]GTPγS) assay. Bifunctional opioids that interact with MOR and DOR, the latter as agonists or antagonists, have been reported to have fewer side-effects than MOR agonists. The p-chlorophenethyl compound 2i was evaluated for its effect on respiration in both mice and squirrel monkeys. Compound 2i did not depress respiration (using normal air) in mice or squirrel monkeys. However, under conditions of hypercapnia (using air mixed with 5% CO2), respiration was depressed in squirrel monkeys.

Keywords: (−)-N-phenethylnorhydromorphone analogs; MOR and DOR agonists; [35S]GTPgammaS assay; bias factor; bifunctional ligands; forskolin-induced cAMP accumulation assays; molecular modeling & simulation; opioid; respiratory depression; β-arrestin recruitment assays.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Prototypical 4,5-epoxymorphinan agonists and antagonists.
Scheme 2
Scheme 2
Synthesis of N-substituted hydromorphones.
Figure 1
Figure 1
Conserved polar/charged residues (in red; numbering as in MOR) that interacted with the -O and -OH groups of the N-phenethylnorhydromorphone body through H-bonds; the body was also stabilized by close packing with four conserved nonpolar residues (blue) through hydrophobic forces. Although not in direct interactions, a few non-conserved residues (green) were seen to interact with the ligands indirectly through short water chains. These residues may thus be important to modulate the behavior of MOR and DOR independently, which may be accomplished through specific substituents that can engage them more directly. Frequencies of contacts were deemed statistically relevant if they were observed at least 25% of the time, except for the critical -NH---D147 distance (MOR) and -NH---D128 distance (DOR) that was required to persist for at least 75% of the time for the conformer to be considered (see details of the analysis in Table S2).
Figure 2
Figure 2
Critical tail-OR interactions of p-F (2e) and -Cl (2i) substituents. (A) p-F (weak partial DOR agonist) vs. p-Cl (potent full DOR agonist); only one of the two conformers of each ligands are shown (see text); (B) p-Cl (potent partial MOR agonists); the two conformers shown. The red lines represent frequent, statistically significant interactions that were obtained from the dynamic simulations. Sequence numbering as in the corresponding ORs.
Figure 3
Figure 3
Effects of morphine and 2i on respiratory rate in mice. After acclimation in observation boxes, mice were injected with either saline, morphine 10 mg/kg, or 2i and connected to a throat sensor. Five min later, the recording was started and respiratory rate was measured from 6 min to 45 min post-injection (A). Area under the curve (AUC) was calculated from 6 min to 45 min. Morphine significantly reduced respiratory rate compared to saline (B). Data are expressed as mean ± standard error of the mean (SEM.) (n = 6–8) (**** p < 0.0001). One-way ANOVA followed by Dunnett’s multiple comparison test.
Figure 4
Figure 4
Effects of 2i on tail withdrawal latency from different temperatures of water (filled symbols) and operant behavior disruption (open symbols) in squirrel monkeys (n = 4). Data are expressed as mean ± SEM (n = 4).
Figure 5
Figure 5
Effects in squirrel monkeys of 2i and morphine on respiratory rate (bottom panels) or on minute volume (top panels) in the presence of normal air (open symbols) or air mixed with 5% CO2 (filled symbols). 2i and morphine significantly reduced minute volume in 5% CO2 without significantly altering respiratory rate. Data are expressed as mean ± SEM. (n = 4); (*) indicates the difference from saline (p ≤ 0.01; one-way ANOVA followed by Dunnett’s multiple comparison test.
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