Relation between Analgetic ED₅₀ Dose and Time-Course Brain Levels of N-Alkylnormeperidine Homologs

The brain levels of meperidine and three N-alkyl homologues were determined at equal analgetic iv doses in mice. The relative levels of the four compounds in brain were found to be closely proportional to their ED₅₀ doses even though the compounds exhibit a wide range in partition coefficient and metabolic N-dealkylation. While lipid solubility and metabolism are undoubtedly important factors in the overall time-course brain levels, it appears that during the period of analgetic measurement (5-60 min after injection) these factors do not profoundly affect the relative brain levels because peak uptake occurs within the first 5 min after administration of the homologues. As a consequence, the observed ED₅₀ potencies appear to provide a fair approximation of the relative receptor affinities of the four homologues. N-Dealkylation was observed as a major metabolic transformation by mouse liver in vivo for all four compounds, and the extent of this N-dealkylation was found to directly correspond to the rates of N-dealkylation by mouse liver homogenate seen in an earlier study.