Analgesic activity in a series of n-substituted ethyl 4-phenylpiperidine-4-carboxylates

Abstract

1. A series of compounds in which the N methyl group of pethidine was replaced - by tertiary amino alkyl and alkyloxyalkyl groups, both carrying a further ether oxygen function, alkyloxyalkyl and aryloxyalkyl groups - has been tested for analgesic activity in rats.

2. The method used for determining the anal ... gesic effect was that of Green and Young {1951) as modified by Millar and Stephenson (1956).

3. A design for a cross~over test is described.

4. Acute and subacute toxicity tests have been performed.

5. The effects of the more active derivative have been studied on the respiration of the rat. Whilst the order of potency was the same as found in the analgesic tests, the difference in potency relative to TAl was not so marked. TA48 is seven times more powerful than TAl as an analgesic but only twice as active as a respiratory depressant.

6. Structure and relationship is discussed.

7. The effect of the more active test analgesics have been studied on the peristaltic reflex of guinea-pig ileum. The results of the test analgesics on this reflex ran parallel to their relative analgesic potencies.

8. Many substances were found to be more active than pethidine. One of these, TA48, N-(tetrahydrofurfuryl oxyethyl) 4--phenyl-4-ethoxycarbonyl piperidine is twenty to fifty times more potent than pethidine and is less than three times as toxic.

9. Some of these derivatives, TA24, TA27, TA28, TA33 and TA48, have been selected as suitable for clinical trials.