Divergent structure activity relationships in series of enkephalin agonists and cognate antagonists.
Diallylation of the amino group of [Leu]enkephalin methyl ester yields a moderately potent, delta-selective opiate receptor antagonist. The diallyl congeners of a larger range of potent mu-and delta-selective enkephalin agonists have been prepared and were found to be weak, non-selective antagonists as assessed by their ability to antagonise the effects of normorphine and [Leu]enkephalin on the field-stimulated mouse vas deferens. Conversely, whereas [Gly3 psi (CH2S)Phe4,Leu5]enkephalin and [Gly3 psi(CH2S)-D-Phe4,Leu5]enkephalin are virtually inactive as opiate agonists the corresponding diallyl analogues are moderately potent, highly selective delta-antagonists. Analogues of diallyl[Leu]enkephalin in which the Gly2 and Gly3 residues have been replaced by D- and L- Ala have also been prepared and tested as delta-receptor antagonists. In addition, the empiric energy program ECEPP has been used to derive eighteen low energy conformations of diallyl[Leu]enkephalin and to estimate the effect of the D- and L-Ala substitutions on the conformer energies. Two conformers were identified for which there was a partial correlation between the variations in conformational energy and delta-antagonist potency.
D000818:Animals; D001681:Biological Assay; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D004745:Enkephalins