Effects of changes in the structure of enkephalins and of narcotic analgesic drugs on their interactions with mu- and delta-receptors.

1 The activity pattern of analogues of the enkephalins was determined in four parallel assays, the inhibition of the electrically evoked contraction of the guinea-pig ileum and mouse vas deferens at 36 degrees C and the inhibition of [(3)H]-naltrexone and [(3)H]-leucine-enkephalin binding at 0 to 4 degrees C in homogenates of guinea-pig brain.2 The activity pattern was best characterized by the ratio of the potency in the guinea-pig ileum to that in the mouse vas deferens (G.p.i./M.v.d.) and the ratio of the potency in inhibiting [(3)H]-naltrexone binding to that in inhibiting [(3)H]-leucine-enkephalin binding (Nal/Leu).3 The enkephalins had low G.p.i./M.v.d. (0.02 to 0.09) and low Nal/Leu (0.05 to 0.18) ratios whereas the corresponding values for morphine were 7.0 and 7.5.4 Analogues obtained by substituting D-Ala for Gly(2) and D-Met or D-Leu for L-Met(5) or L-Leu(5) showed only minor changes in G.p.i./M.v.d. (0.01 to 0.11) and in Nal/Leu (0.06 to 0.13) ratios.5 Analogues in which resistance to enzymatic degradation was brought about by amidation of the C-terminal carboxylic group or methylation of the amino group of tyrosine or both modifications, had G.p.i./M.v.d. ratios of 1.2 to 5.5 and Nal/Leu ratios of 0.5 to 21. High values (2.1 and 3.4) were found for the potent antinociceptive analogue of Sandoz, Tyr-D-Ala-Gly-NCH(3)Phe-Met(O)-ol.6 In the mouse vas deferens, some of the analogues with high G.p.i./M.v.d. and Nal/Leu ratios were tested for antagonism by naloxone and found to require less than the high concentration needed for the natural enkephalins. C57/BL mice, which have a lowered sensitivity to morphine but a normal response to peptides with low G.p.i./M.v.d. and Nal/Leu ratios, had a lowered sensitivity to analogues with high ratios.7 In the alkaloid-like series of narcotic analgesic drugs, ketobemidone, levorphanol, methadone, etorphine and the antagonist Mr 2266 had lower Nal/Leu ratios (1.0 to 2.8) than morphine, normorphine, naloxone and naltrexone (8 to 12).8 It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with delta-receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with mu-receptors. For antinociceptive action mu-receptors may be more important than delta-receptors.