PhD Scientific Days 2025

Pharmaceutical Sciences and Health Technologies I.

Biorelevant Physicochemical Characterization of Morphine Derivatives to Improve Analgesic Selectivity

Name of the presenter

Malik Alaa

Institute/workplace of the presenter

Semmelweis University

Authors

Alaa Malik¹, Prof. Noszál Béla¹, Dr. Mazák Károly¹

1: Semmelweis University, Department of Pharmaceutical Chemistry, Hőgyes E. u. 9., H-1092 Budapest, Hungary

Text of the abstract

Introduction:
Relieving severe pains is an unmet medical need, in which opioids are of prime importance and in the focus of pharmaceutical companies. New derivatives of morphine are systematically synthesized with the aim of separating the advantageous therapeutic properties from the addictive aspects of morphine.

Aims:
The objective of this study is to characterize the physicochemical properties, namely basicity, lipophilicity and permeability of thirty opioid ligands, which include eleven newly synthesized compounds.

Methods:
pH-potentiometry and the shake-flask method were used for the characterization of species-specific basicity and lipophilicity. The effective permeability was determined using a brain-specific parallel artificial membrane permeability assay.

Results:
Structural modifications, namely O-methylation in position 3, isomerization in position 6, saturation of the double bond in position 7, 14-hydroxylation, and the substitution of N-(β-phenylethyl) and N-cyclobutylmethyl side chains all have various effects on these physicochemical properties, and these are explained and compared to computationally predicted values. Computational predictions inadequately capture hydrogen bond formation with the tertiary amino group in case of 14-hydroxylation, just as the effects of hydroxy oxidation at position 6 and N-methyl substitution with N-(β-phenylethyl).

Conclusion:
The relationship between lipophilicity, permeability and potency is presented by lipophilic efficiency plots that reveal the most promising compounds. This study emphasizes the importance of experimental determination of these essential physicochemical parameters, furthermore, it can contribute to a more thorough understanding of the pharmacokinetic properties.

Funding:
This research was funded by the Stipendium Hungaricum scholarship.

Email: alaa.malik@phd.semmelweis.hu
University: Semmelweis University, Department of Pharmaceutical Chemistry, Budapest, Hungary
Supervisor: Prof. Béla Noszál