Phenylpiperidine analgesics

By conventional tests, secondary amine analogues of 4-phenylpiperidine analgesics lack activity (normorphine is equi-potent with morphine by the intra-cisternal route [48]) many secondary bases of the thebaines,(VII), however, are morphine-like analgesics. These findings lend support to the view that the low potencies reported for many nor-analogues of analgesics are due to distribution factors and not to the failure of such derivatives to associate at the receptor. 

The morphine-like potency [100] of the 4-(2-furyl) ether (XXIV) raises the question of the general acceptability or otherwise of a 4-alkoxy group as the C-4 oxygen function in 4-phenylpiperidine analgesics. Comparison of the relative... 

In an analysis of stereochemical factors in narcotic analgesics, Portoghese considers that the conformational requirements for most of the 4-phenylpiperidine analgesics appear to be minimal [282]. His argument was based, in part upon (1) the fact that endo and exo isomeric azabicyclo [2,2,1] heptane analogues (LXXXII) of pethidine have similar orders of potency in mice (benzoquinone... 

The combination of MAOIs with meperidine, and perhaps with other phenylpiperidine analgesics, also has been implicated in fatal reactions attributed to the serotonin syndrome. Aspirin, nonsteroidal anti-inflammatory drugs, and acetaminophen should be used for mild to moderate pain. Of the narcotic agents, codeine and morphine are safe in combination with MAOIs, although doses may need to be lower than usual. 

Further studies of phenolic analogs of 4-phenylpiperidine analgesics— especially those with preferred axial 4-phenyl chair conformations—are therefore clearly important for the elucidation of the ligand-receptor binding modes of derivatives based on pethidine. 

Figure 12.3. Phenylpiperidine analgesics and metabolic activation of MPTP. In efforts to synthesize the meperidine-like analgesic agent MPPP ("designer heroin,") (4), MPTP (3)can be formed. It is converted selectively by monoamine oxidase type B (MAO-B, inhibited by agents including deprenyl (selegiline)and pargylineto MPDP (7), and thence to MPP" (8)the proposed toxic species that accumulated in dopamine neurons to result in disruption of their cellular respiration and death.

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