Deconstructing 14-phenylpropyloxymetopon: minimal requirements for binding to mu opioid receptors

Abstract

A series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized as deconstructed analogs of 14-phenylpropyloxymetopon and analyzed for opioid receptor binding affinity. Using the Conformationally Sampled Pharmacophore modeling approach, we discovered a series of compounds lacking a tyrosine mimetic, historically considered essential for μ opioid binding. Based on the binding studies, we have identified the optimal analogs to be N-methyl-N-phenylpropyl-2-(3-phenylpropoxy)ethanamine, with 1520 nM, and 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine with 1680 nM affinity for the μ opioid receptor. These partial opioid structure analogs will serve as the novel lead compounds for future optimization studies.

Figure 1

Opioids used for hypothesis and the proposed analog

Figure 2

1D probability distribution of distances between the basic nitrogen (N) and the aromatic moieties (X, Y) of compounds 17 and 18. Green represents the probability distribution of the XN distance on the 14-cinnamyloxymetopon (14-COM); red the YN on the 14-cinnamyloxymetopon; blue the YN on 17 and magenta the YN on 18.

Figure 3

1D probability distribution of distances between the basic nitrogen and the aromatic moiety coming off the oxygen on compounds 33–38 and the aromatic A-ring on morphine.

Figure 4

1D probability distribution of distances between the basic nitrogen and the aromatic moiety coming off the nitrogen on compounds 33–38 and the aromatic A-ring on morphine

Scheme 2.1

Synthesis of analogs 3, 5 and 7 and their yields

Scheme 2.2

Synthesis of N,N-dialkyl analogs and their yields

Scheme 2.3

Synthesis of pyrrolidine, piperdine and azepane containing analogs and their yields

Scheme 2.4

Synthesis of N-arylalkyl and N-diallyl analogs and their yields