Comparison of mu-, delta- and kappa-receptor binding sites through pharmacologic evaluation of p-nitrophenylalanine analogs of opioid peptides.
For the purpose of comparing the structural requirements of opioid receptor subsites interacting with phenylalanine residues of opioid peptides, analogs containing p-nitrophenylalanine (Phe(pNO2) ) were synthesized and tested in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assay as well as in mu- and delta-receptor selective binding assays. Whereas substitution of Phe(pNO2) in position 4 of the mu-selective analog H-Tyr-c[-N epsilon-D-Lys-Gly-Phe-Leu-] and of the delta-selective analog H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH produced a significant potency increase in all assays, the corresponding substitution in the kappa-selective dynorphin-(1-13) fragment resulted in a decreased potency in the GPI-assay. These findings suggest that the electronic requirements of the Phe4 binding site at the mu- and delta-receptor are identical, but different from those of the corresponding site at the kappa-receptor. The observation that Phe(pNO2) substitution in position 3 of morphiceptin and dermorphin also produces a drastic potency drop indicates that the Phe3 side-chain of the latter peptides at the mu- and delta-receptor may bind to a site different from that interacting with the Phe4 side-chain of enkephalins.
D000818:Animals; D004723:Endorphins / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D010649:Phenylalanine / Q000031:analogs & derivatives; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D004723:Endorphins; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C040239:4-nitrophenylalanine; D010649:Phenylalanine