Detailed receptor binding studies of a series of N-substituted ethyl 3-arylnipecotates

Receptor-binding studies with [3H]-naloxone and [3H]-DADL have been made for a series of 3-arylpiperidines known to have moderate analgesic agonist and antagonist activities. All analogues were found to bind selectively to the opiate "mu" receptor with affinities consistent with their in vivo activity. However, Na+ did not appreciably alter their IC50 values in competition with [3H]-naloxone, independent of their relative agonist/antagonist activity. This anomaly is consistent with our previous theoretical studies of these 3-phi piperidines which postulated different modes of agonist and antagonist receptor binding than that for fused ring opiates. Computer-assisted analysis of the binding shows that this low IC50 ratio is probably due to a greatly enhanced affinity of these analogues at a third site in the presence of Na+, behavior parallel to that of naloxone.