EFFECTS OF CHANGES IN THE STRUCTURE OF ENKEPHALINS AND OF NARCOTIC ANALGESIC DRUGS ON THEIR INTERACTIONS WITH μ‐ AND δ‐RECEPTORS

Abstract

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°C and the inhibition of [3 H]‐naltrexone and [3 H]‐leucine‐enkephalin binding at 0 to 4°C in homogenates of guinea‐pig brain. 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). 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. 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. 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. 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. 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). It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with δ‐receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with μ‐receptors. For antinociceptive action μ‐receptors may be more important than δ‐receptors.