An Indirect Screen for Brain Uptake of 1,2-Diarylethane Melanocortin 4 Receptor Antagonists in Rats

Antagonism of the melanocortin 4 receptor (MC4R) has been proposed as a therapeutic intervention for the prevention of lean body mass waste, as in cachexia. Pharmacokinetic profiles of substituted 1,2-diarylethane MC4R antagonists were determined in rats after a single intravenous (IV) administration at 1 mg/kg. Brain and plasma concentrations of these compounds were determined at 1 and 4 hours after an oral dose at 10 mg/kg, since oral administration is the intended clinical dosing route and the pharmacological target is the central nervous system. The brain to plasma concentration ratios (0.10 - 50) after oral dosing correlated well with Vdss (2.21 to 81.4 L/kg; R2=0.810) determined after IV administration. A good correlation was also observed between the brain AUC0-4hr (119 - 18400 nM*hr) and Vdss (R2=0.981). Thus, further screening and ranking of substituted 1,2-diarylethanes for their brain uptakes could be carried out more efficiently via the simple and indirect Vdss screen after intravenous administration in rats.