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Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous 1 H NMR-Based log P / D Determination, Both Separately and in Mixtures.

Dina YeffetIshay ColumbusGalit ParvariYoav EichenSigal SaphierLee Ghindes-AzariaOrit Redy-KeisarDafna AmirEyal DrugEytan GershonovIris BinyaminYoram CohenNaama Karton-LifshinYossi Zafrani
Published in: Journal of medicinal chemistry (2024)
A systematic study of trends in the lipophilicity of prominent representatives of the opioid family, including natural, semisynthetic, synthetic, and endogenous neuropeptide opioids, is described. This was enabled by a straightforward 1 H NMR-based log P / D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous log D determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact Δlog D values of matched pairs is required. Interpretation of the experimental Δlog D 7.4 values of selected matched pairs, focusing inter alia on the 3-OMe and 14-OMe motifs in morphinan opioids, is suggested with the aid of DFT calculations and may be useful for the discovery of new opioid therapeutics.
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