PhD Scientific Days 2024

Poster Session R - Pharmaceutical Sciences and Health Technologies 2.

Characterization of opioid agonist morphine derivatives with emphasis on medicinal chemistry

Text of the abstract

Introduction: Relieving of severe pains is an unmet medical need, in which the derivatives of morphine are of prime importance. A thorough understanding of physicochemical properties are crucial to develop new compounds of improved therapeutic properties.

Aim:This study quantifies basicity, lipophilicity and permeability, the biorelevant physicochemical parameters of thirty opioid agonists, including eleven newly synthesized compounds.

Methods: pH-potentiometry and shake-flask method were used to determine species-specific basicity and lipophilicity. Permeability was measured through a brain-specific parallel artificial membrane to predict BBB penetration.

Results: O-methylation in position 3, isomerization in position 6, saturation of the 7,8 double bond, 14-hydroxylation, and the substitution of N-(β-phenylethyl) and N-cyclobutylmethyl side chains all influence these physicochemical properties, which can be interpreted by electron-withdrawing and -sending, hydrogen bonding and solvation effects. 14-hydroxylation, and hydrogen bonding with the tertiary amino group effect remarkably these parameters and can not be assessed by currently available computational predictions. Oxidation of the 6-hydroxyl group and replacement of the N-methyl group with the N-(β-phenylethyl) group also result in significant changes in electron-distribution and the concomitant binding propensities, that in silico programs fail to predict.

Conclusion:
The quantified species-specific charge, charge-distribution and lipofilicity values provide sound means to interpret subtle electronic effects, contributing to the development of more effective pain-relieving drugs.

Funding:
Stipendium Hungaricum scholarship