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Activity profiles of dalargin and its analogues in μ ‐, δ ‐ and κ ‐opioid receptor selective bioassays
Author(s) -
Pencheva Nevena,
Pospišek Jan,
Hauzerova Linda,
Barth Tomislav,
Milanov Peter
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702825
Subject(s) - myenteric plexus , receptor , opioid , (+) naloxone , δ opioid receptor , chemistry , κ opioid receptor , pharmacology , hamster , opioid receptor , endocrinology , medicine , biology , biochemistry , immunohistochemistry
To elucidate the structural features ensuring action of [D‐Ala2, Leu5]‐enkephalyl‐Arg (dalargin), a series of dalargin analogues were tested for their effectiveness in depressing electrically‐evoked contractions of the guinea‐pig myenteric plexus‐longitudinal muscle preparations (μ‐ and κ‐opioid receptors) and the vasa deferentia of the hamster (δ‐opioid receptors), mouse (μ‐, δ‐ and κ‐opioid receptors), rat (similar to μ‐opioid receptors) and rabbit (κ‐opioid receptors). The naloxone K B values in the myenteric plexus were also obtained. [L‐Ala 2 ]‐dalargin was 19 times less potent than dalargin, and its pharmacological activity was peptidase‐sensitive. The ratio of δ‐activity to μ‐activity for [L‐Ala 2 ]‐dalargin was 6.78, and K B was 7.9 n M . This emphasizes the role that D‐configuration of Ala 2 plays in determining the active folding of dalargin molecule as well as in conferring resistance to peptidases. [Met 5 ]‐dalargin was equipotent to dalargin in the myenteric plexus, but was more potent in the vasa deferentia of hamster and mouse ( K B =5.5 n M ). Leu 5 and the interdependence of Leu 5 and D‐Ala 2 are of importance for the selectivity of dalargin for μ‐opioid receptors. Dalarginamide was more potent and selective for μ‐opioid receptors than dalargin, whilst dalarginethylamide, though equipotent to dalarginamide in the myenteric plexus, was more potent at δ‐opioid receptors ( K B =5.0 n M ). [D‐Phe 4 ]‐dalarginamide and N‐Me‐[D‐Phe 4 ]‐dalarginamide were inactive indicating the contribution of L‐configuration of Phe 4 to the pharmacological potency of dalargin. N‐Me‐[L‐Phe 4 ]‐dalarginamide possessed the highest potency and selectivity for μ‐opioid receptors (the ratio of δ‐activity to μ‐activity was 0.00053; K B =2.6 n M ). The CONH 2 terminus combined with the N‐methylation of L‐Phe 4 increased the potency and selectivity of dalargin for μ‐opioid receptors.British Journal of Pharmacology (1999) 128 , 569–576; doi: 10.1038/sj.bjp.0702825