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

Dina Yeffet; Ishay Columbus; Galit Parvari; Yoav Eichen; Sigal Saphier; Lee Ghindes-Azaria; Orit Redy-Keisar; Dafna Amir; Eyal Drug; Eytan Gershonov; Iris Binyamin; Yoram Cohen; Naama Karton-Lifshin; Yossi Zafrani

doi:10.1021/acs.jmedchem.4c01153

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

Dina Yeffet, Ishay Columbus, Galit Parvari, Yoav Eichen, Sigal Saphier, Lee Ghindes-Azaria, Orit Redy-Keisar, Dafna Amir, Eyal Drug, Eytan Gershonov, Iris Binyamin, Yoram Cohen, Naama Karton-Lifshin^*, Yossi Zafrani^*

^*Corresponding author for this work

School of Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

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 ¹H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD_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.

Original language	English
Pages (from-to)	12399-12409
Number of pages	11
Journal	Journal of Medicinal Chemistry
Volume	67
Issue number	14
DOIs	https://doi.org/10.1021/acs.jmedchem.4c01153
State	Published - 25 Jul 2024

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Yeffet, D., Columbus, I., Parvari, G., Eichen, Y., Saphier, S., Ghindes-Azaria, L., Redy-Keisar, O., Amir, D., Drug, E., Gershonov, E., Binyamin, I., Cohen, Y., Karton-Lifshin, N., & Zafrani, Y. (2024). Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous ¹H NMR-Based logP/D Determination, Both Separately and in Mixtures. Journal of Medicinal Chemistry, 67(14), 12399-12409. https://doi.org/10.1021/acs.jmedchem.4c01153

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title = "Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous 1H NMR-Based logP/D Determination, Both Separately and in Mixtures",

abstract = "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 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD7.4 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.",

author = "Dina Yeffet and Ishay Columbus and Galit Parvari and Yoav Eichen and Sigal Saphier and Lee Ghindes-Azaria and Orit Redy-Keisar and Dafna Amir and Eyal Drug and Eytan Gershonov and Iris Binyamin and Yoram Cohen and Naama Karton-Lifshin and Yossi Zafrani",

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Yeffet, D, Columbus, I, Parvari, G, Eichen, Y, Saphier, S, Ghindes-Azaria, L, Redy-Keisar, O, Amir, D, Drug, E, Gershonov, E, Binyamin, I, Cohen, Y, Karton-Lifshin, N & Zafrani, Y 2024, 'Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous ¹H NMR-Based logP/D Determination, Both Separately and in Mixtures', Journal of Medicinal Chemistry, vol. 67, no. 14, pp. 12399-12409. https://doi.org/10.1021/acs.jmedchem.4c01153

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AU - Yeffet, Dina

AU - Columbus, Ishay

AU - Parvari, Galit

AU - Eichen, Yoav

AU - Saphier, Sigal

AU - Ghindes-Azaria, Lee

AU - Redy-Keisar, Orit

AU - Amir, Dafna

AU - Drug, Eyal

AU - Gershonov, Eytan

AU - Binyamin, Iris

AU - Cohen, Yoram

AU - Karton-Lifshin, Naama

AU - Zafrani, Yossi

PY - 2024/7/25

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AB - 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 1H NMR-based logP/D determination method developed for compounds holding at least one aromatic hydrogen atom. Moreover, the new method enables a direct simultaneous logD determination of opioid mixtures, overcoming the high sensitivity of this family to the measurement conditions, which is critical when a determination of the exact ΔlogD values of matched pairs is required. Interpretation of the experimental ΔlogD7.4 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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Addressing the Opioids Lipophilicity Challenge via a Straightforward and Simultaneous ¹H NMR-Based logP/D Determination, Both Separately and in Mixtures

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