A uniform molecular model of delta opioid agonist and antagonist pharmacophore conformations.
On the basis of a model of the pharmacophore conformations of agonist of the delta-opioid receptor the corresponding delta-antagonist conformations were determined by means of force field calculations. The results explain the unusual behavior of several cyclic beta-casomorphin analogues on the molecular level. Thus, for instance, the model helps to understand why Tyr-c[D-Orn-2-Nal-D-Pro-Gly] is a mixed mu-agonist and delta-antagonist. Furthermore, the model is consistent with low energy conformations of other delta-antagonists such as Tyr-Tic-Phe, Tyr-Tic-Phe-Phe, naltrindole and BNTX. The occupation of a special spatial area by bulky groups close to the protonated N-terminus of opioid peptides is assumed to be highly critical for the switch from agonist to antagonist behavior.
Brandt
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Institute of Biochemistry, Martin-Luther-University Halle-Wittenberg, Germany.
D000701:Analgesics, Opioid / Q000737:chemistry*; D004723:Endorphins / Q000737:chemistry; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000737:chemistry*; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D004723:Endorphins; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C021968:beta-casomorphins