Structure-activity relationships of enkephalin analogs at opiate and enkephalin receptors: correlation with analgesia.
We have investigated the influence of physico-chemical parameters (chemical structure and lipophilicity), biochemical properties (catabolism, affinity for 3H-etorphine binding sites and 3H-(D-Ala)2-Leu5-enkephalin amide binding sites) and biological activity in isolated organs (guinea-pig ileum and mouse vas deferens) on the regulation of analgesia induced after intracerebroventricular injection of various enkephalin analogs. The selectivity of these metabolically stable analogs for micro- and beta-receptors, present in guinea-pig ileum and mouse vas deferens respectively, depends on the C-terminal amino acid and also on the nature of the second D-amino-acid. A strong correlation exists between activity in guinea-pig ileum and affinity for 3H-etorphine binding sites suggesting that these sites in rat brain have properties identical to those of micro-receptors characterized in guinea-pig ileum. Similarly, the affinity for 3H-(D-Ala)2-Leu5-enkephalin amide binding sites in mouse brain is correlated to the activity in mouse vas deferens and suggests that central beta-receptors are not different from peripheral beta-receptors. If we consider morphine-like drugs and enkephalin analogs containing the same C-terminal amino acid as the enkephalins, there is a good correlation between activity on micro-receptors (affinity for 3H-etorphine binding sites and activity in guinea-pig ileum) and the antinociceptive activity. These results support the hypothesis that micro-receptors are strongly involved in the analgesic effect. However, when proline is the C-terminal amino acid, the antinociceptive activity was enhanced without any concomitant increase in the affinity. This activity enhancement was the same for each analog and a similar correlation (identical to what was found with other opioid peptides and opiates) could still be established. The reason for such a potentiation of the activity remains to be elucidated.
D000595:Amino Acid Sequence; D000700:Analgesics; D000818:Animals; D004723:Endorphins / Q000494:pharmacology*; D004745:Enkephalins / Q000378:metabolism / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D011957:Receptors, Opioid