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

• Published in: Journal of medicinal chemistry Vol. 67; no. 14; pp. 12399 - 12409
• Main Authors: Yeffet, Dina, Columbus, Ishay, Parvari, Galit, Eichen, Yoav, Saphier, Sigal, Ghindes-Azaria, Lee, Redy-Keisar, Orit, Amir, Dafna, Drug, Eyal, Gershonov, Eytan, Binyamin, Iris, Cohen, Yoram, Karton-Lifshin, Naama, Zafrani, Yossi
• Format: Journal Article
• Language: English
• Published: United States 25.07.2024
• Subjects: Analgesics, Opioid - chemistry; Density Functional Theory; Hydrophobic and Hydrophilic Interactions; Magnetic Resonance Spectroscopy; Molecular Structure; Proton Magnetic Resonance Spectroscopy
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c01153

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 H NMR-based log / determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous log 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 values of matched pairs is required. Interpretation of the experimental Δlog 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.