Structure-activity studies of morphine fragments. II. Synthesis, opiate receptor binding, analgetic activity and conformational studies of 2-R-2(hydroxybenzyl)piperidines

Abstract

In this study, a series of 2-benzyl piperidines, that can be regarded as flexible fragments of fused ring opioids, have been synthesized and their pharmacological and conformational profiles determined. These combined studies reveal that, despite the weak activity of the only analog previously reported, modifications of it can lead to compounds with significant opioid receptor affinity and analgetic activity. Conformational studies of these compounds indicate that they can bind to these receptors in either an phenyl-axial and phenyl-equatorial conformer. Features such as the position of the phenolic OH group, the nature of the other 2-substituent and of the N-substituent appear to modulate receptor recognition and activation. However, the 2-benzyl piperidines do not appear to bind or act at the opioid receptors in the same conformation or orientation as their more rigid fused ring counterparts, the benzomorphans. In general, a change from p-OH to m-OH benzyl analogs reduces efficacy and its is possible that the m-OH analogs could be promising analgesics with low physical dependence liability.